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DNA in Supramolecular Chemistry and Nanotechnology

DNA in Supramolecular Chemistry and Nanotechnology

Edited by

EUGEN STULZUniversity of Southampton UK

GUIDO H CLEVERGeorg‐August University of Goumlttingen Germany

This edition first published 2015copy 2015 John Wiley amp Sons Ltd

Registered OfficeJohn Wiley amp Sons Ltd The Atrium Southern Gate Chichester West Sussex PO19 8SQ United Kingdom

For details of our global editorial offices for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at wwwwileycom

The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright Designs and Patents Act 1988

All rights reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording or otherwise except as permitted by the UK Copyright Designs and Patents Act 1988 without the prior permission of the publisher

Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books

Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names service marks trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book

Limit of LiabilityDisclaimer of Warranty While the publisher and author have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose It is sold on the understanding that the publisher is not engaged in rendering professional services and neither the publisher nor the author shall be liable for damages arising herefrom If professional advice or other expert assistance is required the services of a competent professional should be sought

The advice and strategies contained herein may not be suitable for every situation In view of ongoing research equipment modifications changes in governmental regulations and the constant flow of information relating to the use of experimental reagents equipment and devices the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical piece of equipment reagent or device for among other things any changes in the instructions or indication of usage and for added warnings and precautions The fact that an organization or Website is referred to in this work as a citation andor a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make Further readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read No warranty may be created or extended by any promotional statements for this work Neither the publisher nor the author shall be liable for any damages arising herefrom

Library of Congress Cataloging‐in‐Publication data applied for

ISBN 9781118696866

A catalogue record for this book is available from the British Library

Set in 1012pt Times by SPi Global Pondicherry India

1 2015

DNA in Supramolecular Chemistry and Nanotechnology

DNA in Supramolecular Chemistry and Nanotechnology

Edited by

EUGEN STULZUniversity of Southampton UK

GUIDO H CLEVERGeorg‐August University of Goumlttingen Germany

This edition first published 2015copy 2015 John Wiley amp Sons Ltd

Registered OfficeJohn Wiley amp Sons Ltd The Atrium Southern Gate Chichester West Sussex PO19 8SQ United Kingdom

For details of our global editorial offices for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at wwwwileycom

The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright Designs and Patents Act 1988

All rights reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording or otherwise except as permitted by the UK Copyright Designs and Patents Act 1988 without the prior permission of the publisher

Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books

Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names service marks trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book

Limit of LiabilityDisclaimer of Warranty While the publisher and author have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose It is sold on the understanding that the publisher is not engaged in rendering professional services and neither the publisher nor the author shall be liable for damages arising herefrom If professional advice or other expert assistance is required the services of a competent professional should be sought

The advice and strategies contained herein may not be suitable for every situation In view of ongoing research equipment modifications changes in governmental regulations and the constant flow of information relating to the use of experimental reagents equipment and devices the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical piece of equipment reagent or device for among other things any changes in the instructions or indication of usage and for added warnings and precautions The fact that an organization or Website is referred to in this work as a citation andor a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make Further readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read No warranty may be created or extended by any promotional statements for this work Neither the publisher nor the author shall be liable for any damages arising herefrom

Library of Congress Cataloging‐in‐Publication data applied for

ISBN 9781118696866

A catalogue record for this book is available from the British Library

Set in 1012pt Times by SPi Global Pondicherry India

1 2015

DNA in Supramolecular Chemistry and Nanotechnology

Edited by

EUGEN STULZUniversity of Southampton UK

GUIDO H CLEVERGeorg‐August University of Goumlttingen Germany

This edition first published 2015copy 2015 John Wiley amp Sons Ltd

Registered OfficeJohn Wiley amp Sons Ltd The Atrium Southern Gate Chichester West Sussex PO19 8SQ United Kingdom

For details of our global editorial offices for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at wwwwileycom

The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright Designs and Patents Act 1988

All rights reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording or otherwise except as permitted by the UK Copyright Designs and Patents Act 1988 without the prior permission of the publisher

Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books

Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names service marks trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book

Limit of LiabilityDisclaimer of Warranty While the publisher and author have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose It is sold on the understanding that the publisher is not engaged in rendering professional services and neither the publisher nor the author shall be liable for damages arising herefrom If professional advice or other expert assistance is required the services of a competent professional should be sought

The advice and strategies contained herein may not be suitable for every situation In view of ongoing research equipment modifications changes in governmental regulations and the constant flow of information relating to the use of experimental reagents equipment and devices the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical piece of equipment reagent or device for among other things any changes in the instructions or indication of usage and for added warnings and precautions The fact that an organization or Website is referred to in this work as a citation andor a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make Further readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read No warranty may be created or extended by any promotional statements for this work Neither the publisher nor the author shall be liable for any damages arising herefrom

Library of Congress Cataloging‐in‐Publication data applied for

ISBN 9781118696866

A catalogue record for this book is available from the British Library

Set in 1012pt Times by SPi Global Pondicherry India

1 2015

This edition first published 2015copy 2015 John Wiley amp Sons Ltd

Registered OfficeJohn Wiley amp Sons Ltd The Atrium Southern Gate Chichester West Sussex PO19 8SQ United Kingdom

For details of our global editorial offices for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at wwwwileycom

The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright Designs and Patents Act 1988

All rights reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording or otherwise except as permitted by the UK Copyright Designs and Patents Act 1988 without the prior permission of the publisher

Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books

Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names service marks trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book

Limit of LiabilityDisclaimer of Warranty While the publisher and author have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose It is sold on the understanding that the publisher is not engaged in rendering professional services and neither the publisher nor the author shall be liable for damages arising herefrom If professional advice or other expert assistance is required the services of a competent professional should be sought

The advice and strategies contained herein may not be suitable for every situation In view of ongoing research equipment modifications changes in governmental regulations and the constant flow of information relating to the use of experimental reagents equipment and devices the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical piece of equipment reagent or device for among other things any changes in the instructions or indication of usage and for added warnings and precautions The fact that an organization or Website is referred to in this work as a citation andor a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make Further readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read No warranty may be created or extended by any promotional statements for this work Neither the publisher nor the author shall be liable for any damages arising herefrom

Library of Congress Cataloging‐in‐Publication data applied for

ISBN 9781118696866

A catalogue record for this book is available from the British Library

Set in 1012pt Times by SPi Global Pondicherry India

1 2015

List of Contributors xvPreface xix

Part I (Non‐) Covalently Modified DNA with Novel Functions 1

11 DNA‐Based Construction of Molecular Photonic Devices 3111 Introduction 3112 Using DNA as a template to construct discrete optoelectronic nanostructures 5113 Assembly of photonic arrays based on the molecular recognition of

single‐stranded DNA templates 7114 Assembly of photonic arrays based on the molecular recognition of

double‐stranded DNA templates 101141 Intercalation 101142 Minor‐groove binding 12

115 Towards the construction of photonic devices 13116 Outlook 13

1161 Optoelectronic circuits 131162 Diagnostic platforms 14

References 15

12 π‐Conjugated DNA Binders Optoelectronics Molecular Diagnostics and Therapeutics 22

121 π‐Conjugated compounds 22122 DNA binders for different applications 23

1221 Molecular diagnostics 231222 Therapeutics 261223 Optoelectronics 26

123 Targeting duplex DNA 271231 Examples of π-conjugated compounds interacting with double-stranded

DNA ndash minor groove binders 291232 Examples of π‐conjugated DNA binders interacting with double‐stranded

DNA ndash intercalators 32

Contents

vi Contents

124 Examples of π‐conjugated compounds interacting with hybrid duplexes and higher order nucleic acid structures 321241 Examples of π‐conjugated compounds interacting with DNAbullRNA and

DNAbullPNA hybrid duplexes 331242 Examples of π‐conjugated compounds interacting with higher order

nucleic acid structures 33125 Conclusions 33References 34

13 Metal Ion‐ and Perylene Diimide‐Mediated DNA Architectures 38131 Introduction 38132 Metal ion complexes as DNA modifications hydroquinoline and terpyridine 39133 Perylene diimide‐based DNA architectures 42134 Conclusions 49References 49

14 DNA with Metal‐Mediated Base Pairs 52141 Introduction 52142 Metal‐mediated base pairs with natural nucleobases 53

1421 Pyrimidines 531422 Purines 54

143 Metal‐mediated base pairs with artificial nucleobases 541431 Individual metal‐mediated base pairs 541432 Stacks of metal‐mediated base pairs 581433 Doubly metalated base pairs 59

144 Outlook 61References 61

15 Metal‐Aided Construction of Unusual DNA Structural Motifs 65151 Introduction 65152 DNA duplexes containing metal‐mediated base pairs 66153 Metal‐aided formation of triple‐stranded structures 69154 Metal‐aided formation of four‐stranded structures 71155 Metal‐aided formation of DNA junction structures 73156 Summary and outlook 75References 75

Part II DNA Wires and Electron Transport Through DNA 79

21 Gating Electrical Transport Through DNA 81211 Introduction 81212 DNA structure 82213 Direct electrical measurements of DNA 82214 Gate modulation of current flow in DNA 84215 DNA transistors 86216 Summary and outlook 92References 92

Contents vii

22 Electrical Conductance of DNA Oligomers mdash A Review of Experimental Results 94221 Introduction 94222 DNA structures 95223 Scanning probe microscopy 95

2231 STM break junction 962232 Conductive AFM 96

224 Lithographically defined junctions 982241 Mechanically controllable break junctions 982242 Direct contacts 992243 Carbon nanotube contacts 100

225 Conclusions 101References 102

23 DNA Sensors Using DNA Charge Transport Chemistry 105231 Introduction 105232 DNA‐functionalized electrochemical sensors 107

2321 Redox probes for ground state DNA‐mediated charge transport detection 1092322 Different platforms for DNA electrochemistry 1102323 Detection of single base mutations and DNA lesions 111

233 Detection of DNA‐binding proteins 1112331 Detection of transcriptional regulators 1112332 Methyltransferase and methylation detection 1122333 Photolyase activity and detection 1142334 ATP‐dependent XPD activity on surfaces 114

234 DNA CT within the cell 1152341 DNA CT can occur within biologically relevant environments 115

235 Conclusions 117Acknowledgements 117References 117

24 Charge Transfer in Non‐B DNA with a Tetraplex Structure 121241 Introduction 121242 CT in dsDNA (B‐DNA) 122243 CT in non‐B DNA with a tetraplex structure 123

2431 G‐quadruplex DNA 1232432 i‐motif DNA 127

244 Conclusions 132Acknowledgments 132References 132

Part III Oligonucleotides in Sensing and Diagnostic Applications 137

31 Development of Electrochemical Sensors for DNA Analysis 139311 Introduction 139312 Genosensors based on direct electrocactivity of nucleic bases 140313 Genosensors based on electrochemical mediators 141314 Genosensors based on free diffusional redox markers 142

viii Contents

315 Genosensors incorporating DNA probes modified with redox active molecules ndash lsquosignal‐offrsquo and lsquosignal‐onrsquo working modes 145

316 Genosensors for simultaneous detection of two different DNA targets 151317 Conclusions 154Acknowledgements 154References 154

32 Oligonucleotide Based Artificial Ribonucleases (OBANs) 158321 Introduction 158322 Early development of OBANs 159323 Metal ion based artificial nucleases 159324 Non‐metal ion based systems 161325 Creating bulges in the RNA substrate 162326 PNAzymes and creation of artificial RNA restriction enzymes 164327 Conclusions 167References 168

33 Exploring Nucleic Acid Conformations by Employment of Porphyrin Non‐covalent and Covalent Probes and Chiroptical Analysis 172

331 Introduction 172332 Non‐covalent interaction of porphyrinndashDNA complexes 174

3321 Interaction with single‐stranded DNA 1743322 Double helix conformations B‐ and Z‐DNA 1763323 G‐quadruplex 181

333 Porphyrins covalently linked to DNA 1873331 Porphyrins attached to 5prime‐ and 3prime‐termini of DNA with phosphates and amides 187

33311 5prime‐Phosphate linkage 18733312 Detection of the B‐ to Z‐transition 18933313 3prime‐Amide linkage 19133314 5prime‐Amide linkage 192

3332 Capping effect 1933333 Porphyrin C-nucleoside replacement of natural nucleobases 1973334 Porphyrins embedded in the backbone of DNA 1973335 Diastereochemically pure anionic porphyrinndashDNA dimers 1983336 Incorporation of rigid and flexible linked porphyrins to DNA nucleobases 200

334 Conclusions 203References 203

34 Chemical Reactions Controlled by Nucleic Acids and their Applications for Detection of Nucleic Acids in Live Cells 209

341 Introduction 209342 Intracellular nucleic acid targets 211343 Methods for monitoring ribonucleic acids in live cells 211

3431 Genetically encoded reporters 2123432 Hybridization‐responsive oligonucleotide probes 213

Contents ix

3433 Fluorogenic templated reactions 21434331 Nucleophilic substitution reactions 21434332 Staudinger reduction 216

3434 Photochemical reactions 221344 Perspectives 225References 226

35 The Biotechnological Applications of G‐Quartets 229351 Introduction 229352 Nucleobases and H‐bonds 229353 Duplex‐DNA mimics 231354 Guanine and G‐quartets 232355 G‐Quartets and G‐quadruplexes 232

3551 Colorimetric detection 2343552 Luminescencendashfluorescence detection 2343553 Electrochemical detection 235

356 Quadruplex‐DNA mimics 2363561 Intermolecular SQ G‐monomers 2363562 Intermolecular interconnected SQ G‐dimers 2393563 Intramolecular SQ (or iSQ) G‐tetramers 240

357 Conclusions 244References 244

Part IV Conjugation of DNA with Biomolecules and Nanoparticles 247

41 Nucleic Acid Controlled Reactions on Large Nucleic Acid Templates 249411 Introduction 249412 Nucleic acid controlled chemical reactions 250413 Applications 257

4131 Reactions on intracellular RNA 2574132 Reactions on large biogenic DNA and RNA templates in vitro 2594133 Drug screening 2624134 Materials science 266

414 Conclusions 268References 270

42 Lipid Oligonucleotide Bioconjugates Applications in Medicinal Chemistry 276421 Introduction 276422 Chemical approach to the synthesis of lipidndasholigonucleotide conjugates 277

4221 Solid‐phase (or pre‐synthetic) approach 27742211 Lipid conjugation at the 3ʹ‐terminal 27742212 Lipid conjugation at 5ʹ‐terminal 28042213 Lipid conjugation at internal position (intra‐chain) 282

4222 Solution‐phase (or post‐synthetic) approach 284

x Contents

423 Biomedical applications 2864231 LONs as efficient delivery vehicles in gene therapy 2864232 Other biomedical applications of LONs 288

424 Conclusions 288Acknowledgements 289References 289

43 Amphiphilic PeptidylndashRNA 294431 Introduction 294432 Three souls alas are dwelling in my breast [2] 295433 Why RNA Why peptides 296434 Hydrolysis‐resistant amphiphilic 3ʹ‐peptidylndashRNA 297435 Synthetic strategy 299436 Prosrsquon cons 300437 Alternative methods and strategies 302438 Molecular properties 302439 Supramolecular properties 3024310 Conclusions and perspectives 304Acknowledgements 306References 306

44 Oligonucleotide‐Stabilized Silver Nanoclusters 308441 Introduction 308442 Sensors 311

4421 Metallic sensors 3114422 Small molecule sensors 3124423 Protein sensors 3134424 Nucleic acid sensors 316

44241 DNA sensors 31744242 MiRNAs sensors 319

4425 Cells 320443 DNA computing (logic gates) 321444 Assorted examples 322445 Conclusions 323References 323

Part V Alternative DNA Structures Switches and Nanomachines 329

51 Structure and Stabilization of CGC+ Triplex DNA 331511 Introduction 331512 Classification of DNA triplets 332513 Structure of triplexes 332514 Triplex stabilizing factors 334

5141 Effect of pH on the triplex 3355142 Effect of cations on the triplex 3355143 Effect of length and composition of the three strands on the triplex 3365144 Molecular crowding 337

Contents xi

515 Formation of stable CGC+ triplex DNA 3375151 Analogues mimicking protonated cytosine 3375152 Analogues with increased pK

a 339

5153 Backbone modification 3405154 Triplex binding ligands 3415155 Other stabilizing effects 344

51551 Polyamines 34451552 Basic oligopeptides 34451553 Silver ions and silver nanoclusters 34551554 Single‐walled carbon nanotubes 346

516 Summary 346References 346

52 Synthetic Molecules as Guides for DNA Nanostructure Formation 353521 Introduction 353522 Covalent insertion of synthetic molecules into DNA 353

5221 Incorporating organic molecules into DNA 3545222 Adjusting flexibility 354

52221 Mediating DNA self‐assembly 3555223 Direct effect of synthetic organic linkers on DNA stability and assembly 357

52231 Supramolecular assembly guided through synthetic additions to DNA 35952232 Backbone insertion of metal binding organic molecules 359

523 Non‐covalently guided DNA assembly 3645231 DNA intercalators 3645232 Groove binding 367

524 Conclusions 369References 369

53 DNA‐Based Nanostructuring with Branched Oligonucleotide Hybrids 375531 Introduction 375532 Branched oligonucleotides 377533 Hybrids with rigid cores 378534 Second‐generation hybrids with a rigid core 382535 Solution‐phase syntheses Synthetic challenges 385536 Hybrid materials 389537 Outlook 392538 Conclusions 394Acknowledgements 394References 394

54 DNA‐Controlled Assembly of Soft Nanoparticles 397541 Introduction 397542 Sequence design 399

5421 Double membrane anchor ssDNA design 3995422 Single membrane anchor multiple ssDNA design 3995423 Single membrane anchor multiple ssDNA design for irreversible

assembly (fusionhemifusion) 400

xii Contents

543 Lipid membrane anchors 400544 DNA‐controlled assembly studied by UV spectroscopy 402

5441 Thermal stability of lipid‐modified DNA conjugates 4045442 DNA mismatch discrimination studies 405

545 Assembly on solid support 406546 Assembly of giant unilamellar liposomes (GUVs) 408547 Conclusions 409Acknowledgements 409References 409

55 Metal Ions in Ribozymes and Riboswitches 412551 Introduction 412552 Coordination chemistry of RNA 413553 Ribozymes 415

5531 Overview of the ribozyme world 4155532 Small ribozymes 4155533 Large ribozymes 417

554 Riboswitches 4205541 Overview of the riboswitch world 4205542 Metal ions assisting riboswitch folding and ligand recognition 4225543 Riboswitch ligands containing a metal 423

55431 Mg2+‐sensing riboswitches 42355432 B

12‐riboswitches 424

55433 MoCoTuCo‐riboswitches 425555 Summary 425Acknowledgement 426References 426

56 DNA Switches and Machines 434561 Introduction 434562 Ion‐stimulated and photonicelectrical‐triggered DNA switches 438

5621 Ion‐stimulated DNA switches 4385622 Photonic and electrical triggering of DNA switches 443

563 Switchable DNA machines 4475631 Two‐state switchable DNA machines 4485632 Multi‐state DNA machines 455

564 Applications of DNA switches and machines 459565 Conclusions and perspectives 466References 467

57 DNA‐Based Asymmetric Catalysis 474571 Introduction 474572 Concept of DNA‐based asymmetric catalysis 474573 Design approaches in DNA‐based asymmetric catalysis 475574 Covalent anchoring 476

Contents xiii

575 Supramolecular anchoring 4785751 First generation DNA‐based catalysts 4785752 Improvement of the catalytic system ndash second generation catalysts 4785753 Catalytic scope of DNA‐based catalysts 479

57531 Conjugated addition reactions 48057532 Miscellaneous reactions 483

5754 Mechanistic studies and role of DNA in catalysis 48457541 DielsndashAlder cycloaddition 48557542 FriedelndashCrafts reaction 48657543 Michael addition 48657544 Hydration of enones 48757545 Stereochemistry in DNA‐based catalytic asymmetric reactions 487

576 Conclusions and perspectives 488References 489

Index 491

Philippe BartheacuteleacutemyUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Jacqueline K BartonDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Nina BerovaDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

Glenn A BurleyDepartment of Pure and Applied ChemistryUniversity of StrathclydeGlasgow UK

Niklaas J BuurmaPhysical Organic Chemistry CentreSchool of ChemistryCardiff UniversityCardiff UK

Jungkweon ChoiThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Jean‐Louis DupreyGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Alessandro DrsquoUrsoDepartment of ScienceUniversity of CataniaCatania Sicily Italy

George A EllestadDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

A ErbeHelmholtz‐Zentrum Dresden‐RossendorfInstitute of Ion Beam Physics and Materials ResearchDivision Scaling PhenomenaDresden Germany

Maria Elena FragalagraveDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Ariel L FurstDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

List of Contributors

xvi List of Contributors

Sofia GalloDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alice GhidiniKarolinska InstituteDepartment of Biosciences and NutritionNovum Sweden

Arnaud GissotUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Andrea GreschnerDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Helmut GriesserInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Michael A GrodickDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Anika KernDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

Alfonso LatorreInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Chun‐Hua LuInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Tetsuro MajimaThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Andriy MokhirFriedrich‐Alexander‐University Erlangen‐NuumlrnbergDepartment of Chemistry and PharmacyGermany

David MonchaudICMUB (Institut de Chimie Moleculaire Universite de Bourgogne)CNRS UMR6302Dijon France

Jens MuumlllerInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Merita MurtolaKarolinska InstituteDepartment of Biosciences and NutritionNovum Swedenand Department of ChemistryUniversity of TurkuTurku Finland

Anastasia MusiariDepartment of ChemistryUniversity of ZurichZurich Switzerland

List of Contributors xvii

Khalid OumzilUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Amit PatwaUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Ana G PetrovicDepartment of ChemistryColumbia UniversityHavemeyer Halland Department of Life SciencesNew York Institute of Technology (NYIT)New YorkNY USA

Fang PuLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Roberto PurrelloDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Hanna RadeckaDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jerzy RadeckiDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jinsong RenLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Clemens RichertInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Ana Rioz‐MartiacutenezStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Gerard RoelfesStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Fiora RosatiDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Magdalena Rowinska‐ZyrekDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alexander SchwengerInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Oliver SeitzDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

xviii List of Contributors

Mitsuhiko ShionoyaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Roland K O SigelDepartment of ChemistryUniversity of ZurichZurich Switzerland

Indranil SinhaInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Hanadi SleimanDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Aacutelvaro SomozaInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Peter StrazewskiInstitut de Chimie et Biochimie Moleacuteculaires et Supramoleacuteculaires (UMR 5246)Universiteacute de LyonLyon France

Roger StroumlmbergKarolinska InstituteDepartment of Biosciences and NutritionNovumSweden

Claudia StubinitzkyKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Yusuke TakezawaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Manuel A TamargoDepartment of ChemistryColumbia UniversityHavemeyer HallNew York NYUSA

Stefan VogelDepartment of PhysicsChemistry and PharmacyUniversity of Southern DenmarkBiomolecular Nanoscale Engineering Center (BioNEC)Denmark

Hans‐Achim WagenknechtKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Fuan WangInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Christian WellnerKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Itamar WillnerInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Kazushige YamanaDepartment of Materials Science and ChemistryUniversity of HyogoHimeji Japan

Notably one of the most influential scientific achievements of the last century concerns the structural elucidation of DNA by Watson Crick Franklin and Wilkins in 1953 [1] As was foreseen in their seminal papers the structure of DNA had profound implications on molecular biology

ldquoWe wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA) This structure has novel features which are of considerable biological interestrdquo

Since then the role of DNA in biology has been accepted as that of the bearer of the genetic code and many genomic sequences have been deciphered including the human genome However the story is far from over and many questions still remain to be answered in particular the details of how DNA works to fulfil its duties including the sequence dependent local structure protein binding to DNA regulation of gene expression (including methylation and selective unwinding from histones) to name but a few Also although knowledge of the three‐letter genetic code allows for the identification of genes and comparison between species to find similarities and heritage it also raises the question of the exact role of the non‐ coding regions of the genomes

Not long after the huge biological importance of DNA had been understood the fascinating features of this self‐assembled biopolymer began to inspire synthetic chemists analytical specialists biophysicists and even computer programmers to devote their research efforts to oligonucleotide‐based systems

The basic principle of the workings of DNA is simple the molecule forms a well‐understood double helix through the complementary base pairing of two antiparallel strands Yet there is far more to DNA than just this concept DNA can act both as a rigid stick (duplex) with a persistence length of about 40ndash50 nm and as a flexible glue (single strand) giving rise to a Lego‐like building block system for the creation of architectures with nanometre precision In addition more complex tertiary structures such as loops triple strands quadru-plexes and various junctions many of which have been found in vivo add to the countless possibilities of creating DNA structures with functions beyond those of just information storage and heredity The plethora of non‐duplex tertiary structures is even more pronounced in the RNA context

By taking DNA out of its biological environment new systems have emerged that are beginning to play a major role in materials science electronics diagnostics medicinal chemistry and much more The supramo-lecular aspects of DNA have seen significant advances in the past few decades particularly with the inclusion of modified nucleotides

Organic synthesis has and will remain a key aspect of DNA chemistry The concept of phosphoramidite chemistry for automated solid‐phase synthesis (SPS) of DNA as first described by Caruthers in 1981 [2] has on the whole remained unaltered as it has proven to be a most versatile approach In principle any diol can

Preface

xx Preface

be used for the stepwise build‐up of functional molecules as the concept is not restricted to nucleosides provided the other functional groups that are present are compatible with the strongly acidic basic and oxidising environment in SPS although milder conditions are also available In addition nucleosides can be chemically functionalised with almost any additional group be it small organic molecules or large metal complexes The combination of all accessible building blocks has lead to a system that is now being explored in almost all areas of science as mentioned earlier

The chapters in this book present an excellent collection of state‐of‐the‐art reviews covering research that is currently being carried out The chapters are devoted to the most important fields being studied

1 (Non‐) covalently modified DNA with novel functions2 DNA wires and electron transport through DNA3 Oligonucleotides in sensing and diagnostic applications4 Conjugation of DNA with biomolecules and nanoparticles5 Alternative DNA structures switches and nanomachines

Each chapter is devoted to a specialised topic within the larger context of DNA chemistry and will give the reader both an introduction to the field and the relevant technologies and a more focussed description of the authorsrsquo own research and viewpoint General conclusions and outlooks for the future are also given We are in the very lucky position of having been able to attract many of the key players in the relevant areas to devote their time to writing what we believe is an outstanding collection of well written and up‐to‐date chapters As the field is growing so rapidly it would be beyond the scope of any textbook to include everyone currently working in this field or to mention the excellent new ideas of every research group This demonstrates that applied DNA technology has reached the level at which it is playing a key role across the board

Nucleotide technology is a fast moving area where research is advancing rapidly However these chapters will certainly remain a key collection for some years to come Even though the systems will steadily improve the basic technologies presented and discussed here will remain the same for the foreseeable future as can be seen from the basic SPS principles The book is intended to give the novice an introduction and a basic overview of all aspects of nucleotide technology including strategies concepts and visions The experienced reader will have an up‐to‐date volume at hand where ndash through the amalgamation of very different ideas ndash novel applications and concepts may be conceived We are therefore convinced that this collection will be very useful to scientists at all levels and we hope that it will indeed trigger the emergence of new research

It is generally difficult if not impossible to predict where the future will take us as new results are being published on a daily basis sometimes in unrelated fields where the impact on onersquos own research may not be immediately evident Many of the approaches used today could not have been predicted ten years ago as some of the key technologies were not available then (eg DNA origami) DNA technology will continue to be important at both the giving and receiving ends DNA bio-nanotechnology will influence material medicinal and biological sciences whereas inventions and demands from those fields will have an impact on the direction of the development of DNA technology

We give great thanks to all contributors to this book and hope that the reader will enjoy it as much as we did during the editorial stages

Eugen StulzGuido H Clever

Preface xxi

References

[1] (a) R E Franklin and R G Gosling Molecular configuration in sodium thymonucleate Nature 1953 171 (4356) 740ndash741 (b) J D Watson and F H C Crick Molecular structure of nucleic acids A structure for deoxyribose nucleic acid Nature 1953 171 (4356) 737ndash738 (c) M H Wilkins A R Stokes and H R Wilson Molecular structure of nucleic acids Molecular structure of deoxypentose nucleic acids Nature 1953 171 (4356) 738ndash740

[2] (a) S L Beaucage and M H Caruthers Deoxynucleoside phosphoramidites ndash A new class of key intermediates for deoxypolynucleotide synthesis Tetrahedron Lett 1981 22 (20) 1859ndash1862 (b) M D Matteucci and M H and Caruthers Nucleotide Chemistry 4 Synthesis of deoxyoligonucleotides on a polymer support J Am Chem Soc 1981 103 (11) 3185ndash3191

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

vi Contents

124 Examples of π‐conjugated compounds interacting with hybrid duplexes and higher order nucleic acid structures 321241 Examples of π‐conjugated compounds interacting with DNAbullRNA and

DNAbullPNA hybrid duplexes 331242 Examples of π‐conjugated compounds interacting with higher order

nucleic acid structures 33125 Conclusions 33References 34

13 Metal Ion‐ and Perylene Diimide‐Mediated DNA Architectures 38131 Introduction 38132 Metal ion complexes as DNA modifications hydroquinoline and terpyridine 39133 Perylene diimide‐based DNA architectures 42134 Conclusions 49References 49

14 DNA with Metal‐Mediated Base Pairs 52141 Introduction 52142 Metal‐mediated base pairs with natural nucleobases 53

1421 Pyrimidines 531422 Purines 54

143 Metal‐mediated base pairs with artificial nucleobases 541431 Individual metal‐mediated base pairs 541432 Stacks of metal‐mediated base pairs 581433 Doubly metalated base pairs 59

144 Outlook 61References 61

15 Metal‐Aided Construction of Unusual DNA Structural Motifs 65151 Introduction 65152 DNA duplexes containing metal‐mediated base pairs 66153 Metal‐aided formation of triple‐stranded structures 69154 Metal‐aided formation of four‐stranded structures 71155 Metal‐aided formation of DNA junction structures 73156 Summary and outlook 75References 75

Part II DNA Wires and Electron Transport Through DNA 79

21 Gating Electrical Transport Through DNA 81211 Introduction 81212 DNA structure 82213 Direct electrical measurements of DNA 82214 Gate modulation of current flow in DNA 84215 DNA transistors 86216 Summary and outlook 92References 92

Contents vii

22 Electrical Conductance of DNA Oligomers mdash A Review of Experimental Results 94221 Introduction 94222 DNA structures 95223 Scanning probe microscopy 95

2231 STM break junction 962232 Conductive AFM 96

224 Lithographically defined junctions 982241 Mechanically controllable break junctions 982242 Direct contacts 992243 Carbon nanotube contacts 100

225 Conclusions 101References 102

23 DNA Sensors Using DNA Charge Transport Chemistry 105231 Introduction 105232 DNA‐functionalized electrochemical sensors 107

2321 Redox probes for ground state DNA‐mediated charge transport detection 1092322 Different platforms for DNA electrochemistry 1102323 Detection of single base mutations and DNA lesions 111

233 Detection of DNA‐binding proteins 1112331 Detection of transcriptional regulators 1112332 Methyltransferase and methylation detection 1122333 Photolyase activity and detection 1142334 ATP‐dependent XPD activity on surfaces 114

234 DNA CT within the cell 1152341 DNA CT can occur within biologically relevant environments 115

235 Conclusions 117Acknowledgements 117References 117

24 Charge Transfer in Non‐B DNA with a Tetraplex Structure 121241 Introduction 121242 CT in dsDNA (B‐DNA) 122243 CT in non‐B DNA with a tetraplex structure 123

2431 G‐quadruplex DNA 1232432 i‐motif DNA 127

244 Conclusions 132Acknowledgments 132References 132

Part III Oligonucleotides in Sensing and Diagnostic Applications 137

31 Development of Electrochemical Sensors for DNA Analysis 139311 Introduction 139312 Genosensors based on direct electrocactivity of nucleic bases 140313 Genosensors based on electrochemical mediators 141314 Genosensors based on free diffusional redox markers 142

viii Contents

315 Genosensors incorporating DNA probes modified with redox active molecules ndash lsquosignal‐offrsquo and lsquosignal‐onrsquo working modes 145

316 Genosensors for simultaneous detection of two different DNA targets 151317 Conclusions 154Acknowledgements 154References 154

32 Oligonucleotide Based Artificial Ribonucleases (OBANs) 158321 Introduction 158322 Early development of OBANs 159323 Metal ion based artificial nucleases 159324 Non‐metal ion based systems 161325 Creating bulges in the RNA substrate 162326 PNAzymes and creation of artificial RNA restriction enzymes 164327 Conclusions 167References 168

33 Exploring Nucleic Acid Conformations by Employment of Porphyrin Non‐covalent and Covalent Probes and Chiroptical Analysis 172

331 Introduction 172332 Non‐covalent interaction of porphyrinndashDNA complexes 174

3321 Interaction with single‐stranded DNA 1743322 Double helix conformations B‐ and Z‐DNA 1763323 G‐quadruplex 181

333 Porphyrins covalently linked to DNA 1873331 Porphyrins attached to 5prime‐ and 3prime‐termini of DNA with phosphates and amides 187

33311 5prime‐Phosphate linkage 18733312 Detection of the B‐ to Z‐transition 18933313 3prime‐Amide linkage 19133314 5prime‐Amide linkage 192

3332 Capping effect 1933333 Porphyrin C-nucleoside replacement of natural nucleobases 1973334 Porphyrins embedded in the backbone of DNA 1973335 Diastereochemically pure anionic porphyrinndashDNA dimers 1983336 Incorporation of rigid and flexible linked porphyrins to DNA nucleobases 200

334 Conclusions 203References 203

34 Chemical Reactions Controlled by Nucleic Acids and their Applications for Detection of Nucleic Acids in Live Cells 209

341 Introduction 209342 Intracellular nucleic acid targets 211343 Methods for monitoring ribonucleic acids in live cells 211

3431 Genetically encoded reporters 2123432 Hybridization‐responsive oligonucleotide probes 213

Contents ix

3433 Fluorogenic templated reactions 21434331 Nucleophilic substitution reactions 21434332 Staudinger reduction 216

3434 Photochemical reactions 221344 Perspectives 225References 226

35 The Biotechnological Applications of G‐Quartets 229351 Introduction 229352 Nucleobases and H‐bonds 229353 Duplex‐DNA mimics 231354 Guanine and G‐quartets 232355 G‐Quartets and G‐quadruplexes 232

3551 Colorimetric detection 2343552 Luminescencendashfluorescence detection 2343553 Electrochemical detection 235

356 Quadruplex‐DNA mimics 2363561 Intermolecular SQ G‐monomers 2363562 Intermolecular interconnected SQ G‐dimers 2393563 Intramolecular SQ (or iSQ) G‐tetramers 240

357 Conclusions 244References 244

Part IV Conjugation of DNA with Biomolecules and Nanoparticles 247

41 Nucleic Acid Controlled Reactions on Large Nucleic Acid Templates 249411 Introduction 249412 Nucleic acid controlled chemical reactions 250413 Applications 257

4131 Reactions on intracellular RNA 2574132 Reactions on large biogenic DNA and RNA templates in vitro 2594133 Drug screening 2624134 Materials science 266

414 Conclusions 268References 270

42 Lipid Oligonucleotide Bioconjugates Applications in Medicinal Chemistry 276421 Introduction 276422 Chemical approach to the synthesis of lipidndasholigonucleotide conjugates 277

4221 Solid‐phase (or pre‐synthetic) approach 27742211 Lipid conjugation at the 3ʹ‐terminal 27742212 Lipid conjugation at 5ʹ‐terminal 28042213 Lipid conjugation at internal position (intra‐chain) 282

4222 Solution‐phase (or post‐synthetic) approach 284

x Contents

423 Biomedical applications 2864231 LONs as efficient delivery vehicles in gene therapy 2864232 Other biomedical applications of LONs 288

424 Conclusions 288Acknowledgements 289References 289

43 Amphiphilic PeptidylndashRNA 294431 Introduction 294432 Three souls alas are dwelling in my breast [2] 295433 Why RNA Why peptides 296434 Hydrolysis‐resistant amphiphilic 3ʹ‐peptidylndashRNA 297435 Synthetic strategy 299436 Prosrsquon cons 300437 Alternative methods and strategies 302438 Molecular properties 302439 Supramolecular properties 3024310 Conclusions and perspectives 304Acknowledgements 306References 306

44 Oligonucleotide‐Stabilized Silver Nanoclusters 308441 Introduction 308442 Sensors 311

4421 Metallic sensors 3114422 Small molecule sensors 3124423 Protein sensors 3134424 Nucleic acid sensors 316

44241 DNA sensors 31744242 MiRNAs sensors 319

4425 Cells 320443 DNA computing (logic gates) 321444 Assorted examples 322445 Conclusions 323References 323

Part V Alternative DNA Structures Switches and Nanomachines 329

51 Structure and Stabilization of CGC+ Triplex DNA 331511 Introduction 331512 Classification of DNA triplets 332513 Structure of triplexes 332514 Triplex stabilizing factors 334

5141 Effect of pH on the triplex 3355142 Effect of cations on the triplex 3355143 Effect of length and composition of the three strands on the triplex 3365144 Molecular crowding 337

Contents xi

515 Formation of stable CGC+ triplex DNA 3375151 Analogues mimicking protonated cytosine 3375152 Analogues with increased pK

a 339

5153 Backbone modification 3405154 Triplex binding ligands 3415155 Other stabilizing effects 344

51551 Polyamines 34451552 Basic oligopeptides 34451553 Silver ions and silver nanoclusters 34551554 Single‐walled carbon nanotubes 346

516 Summary 346References 346

52 Synthetic Molecules as Guides for DNA Nanostructure Formation 353521 Introduction 353522 Covalent insertion of synthetic molecules into DNA 353

5221 Incorporating organic molecules into DNA 3545222 Adjusting flexibility 354

52221 Mediating DNA self‐assembly 3555223 Direct effect of synthetic organic linkers on DNA stability and assembly 357

52231 Supramolecular assembly guided through synthetic additions to DNA 35952232 Backbone insertion of metal binding organic molecules 359

523 Non‐covalently guided DNA assembly 3645231 DNA intercalators 3645232 Groove binding 367

524 Conclusions 369References 369

53 DNA‐Based Nanostructuring with Branched Oligonucleotide Hybrids 375531 Introduction 375532 Branched oligonucleotides 377533 Hybrids with rigid cores 378534 Second‐generation hybrids with a rigid core 382535 Solution‐phase syntheses Synthetic challenges 385536 Hybrid materials 389537 Outlook 392538 Conclusions 394Acknowledgements 394References 394

54 DNA‐Controlled Assembly of Soft Nanoparticles 397541 Introduction 397542 Sequence design 399

5421 Double membrane anchor ssDNA design 3995422 Single membrane anchor multiple ssDNA design 3995423 Single membrane anchor multiple ssDNA design for irreversible

assembly (fusionhemifusion) 400

xii Contents

543 Lipid membrane anchors 400544 DNA‐controlled assembly studied by UV spectroscopy 402

5441 Thermal stability of lipid‐modified DNA conjugates 4045442 DNA mismatch discrimination studies 405

545 Assembly on solid support 406546 Assembly of giant unilamellar liposomes (GUVs) 408547 Conclusions 409Acknowledgements 409References 409

55 Metal Ions in Ribozymes and Riboswitches 412551 Introduction 412552 Coordination chemistry of RNA 413553 Ribozymes 415

5531 Overview of the ribozyme world 4155532 Small ribozymes 4155533 Large ribozymes 417

554 Riboswitches 4205541 Overview of the riboswitch world 4205542 Metal ions assisting riboswitch folding and ligand recognition 4225543 Riboswitch ligands containing a metal 423

55431 Mg2+‐sensing riboswitches 42355432 B

12‐riboswitches 424

55433 MoCoTuCo‐riboswitches 425555 Summary 425Acknowledgement 426References 426

56 DNA Switches and Machines 434561 Introduction 434562 Ion‐stimulated and photonicelectrical‐triggered DNA switches 438

5621 Ion‐stimulated DNA switches 4385622 Photonic and electrical triggering of DNA switches 443

563 Switchable DNA machines 4475631 Two‐state switchable DNA machines 4485632 Multi‐state DNA machines 455

564 Applications of DNA switches and machines 459565 Conclusions and perspectives 466References 467

57 DNA‐Based Asymmetric Catalysis 474571 Introduction 474572 Concept of DNA‐based asymmetric catalysis 474573 Design approaches in DNA‐based asymmetric catalysis 475574 Covalent anchoring 476

Contents xiii

575 Supramolecular anchoring 4785751 First generation DNA‐based catalysts 4785752 Improvement of the catalytic system ndash second generation catalysts 4785753 Catalytic scope of DNA‐based catalysts 479

57531 Conjugated addition reactions 48057532 Miscellaneous reactions 483

5754 Mechanistic studies and role of DNA in catalysis 48457541 DielsndashAlder cycloaddition 48557542 FriedelndashCrafts reaction 48657543 Michael addition 48657544 Hydration of enones 48757545 Stereochemistry in DNA‐based catalytic asymmetric reactions 487

576 Conclusions and perspectives 488References 489

Index 491

Philippe BartheacuteleacutemyUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Jacqueline K BartonDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Nina BerovaDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

Glenn A BurleyDepartment of Pure and Applied ChemistryUniversity of StrathclydeGlasgow UK

Niklaas J BuurmaPhysical Organic Chemistry CentreSchool of ChemistryCardiff UniversityCardiff UK

Jungkweon ChoiThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Jean‐Louis DupreyGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Alessandro DrsquoUrsoDepartment of ScienceUniversity of CataniaCatania Sicily Italy

George A EllestadDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

A ErbeHelmholtz‐Zentrum Dresden‐RossendorfInstitute of Ion Beam Physics and Materials ResearchDivision Scaling PhenomenaDresden Germany

Maria Elena FragalagraveDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Ariel L FurstDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

List of Contributors

xvi List of Contributors

Sofia GalloDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alice GhidiniKarolinska InstituteDepartment of Biosciences and NutritionNovum Sweden

Arnaud GissotUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Andrea GreschnerDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Helmut GriesserInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Michael A GrodickDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Anika KernDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

Alfonso LatorreInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Chun‐Hua LuInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Tetsuro MajimaThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Andriy MokhirFriedrich‐Alexander‐University Erlangen‐NuumlrnbergDepartment of Chemistry and PharmacyGermany

David MonchaudICMUB (Institut de Chimie Moleculaire Universite de Bourgogne)CNRS UMR6302Dijon France

Jens MuumlllerInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Merita MurtolaKarolinska InstituteDepartment of Biosciences and NutritionNovum Swedenand Department of ChemistryUniversity of TurkuTurku Finland

Anastasia MusiariDepartment of ChemistryUniversity of ZurichZurich Switzerland

List of Contributors xvii

Khalid OumzilUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Amit PatwaUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Ana G PetrovicDepartment of ChemistryColumbia UniversityHavemeyer Halland Department of Life SciencesNew York Institute of Technology (NYIT)New YorkNY USA

Fang PuLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Roberto PurrelloDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Hanna RadeckaDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jerzy RadeckiDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jinsong RenLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Clemens RichertInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Ana Rioz‐MartiacutenezStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Gerard RoelfesStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Fiora RosatiDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Magdalena Rowinska‐ZyrekDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alexander SchwengerInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Oliver SeitzDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

xviii List of Contributors

Mitsuhiko ShionoyaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Roland K O SigelDepartment of ChemistryUniversity of ZurichZurich Switzerland

Indranil SinhaInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Hanadi SleimanDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Aacutelvaro SomozaInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Peter StrazewskiInstitut de Chimie et Biochimie Moleacuteculaires et Supramoleacuteculaires (UMR 5246)Universiteacute de LyonLyon France

Roger StroumlmbergKarolinska InstituteDepartment of Biosciences and NutritionNovumSweden

Claudia StubinitzkyKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Yusuke TakezawaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Manuel A TamargoDepartment of ChemistryColumbia UniversityHavemeyer HallNew York NYUSA

Stefan VogelDepartment of PhysicsChemistry and PharmacyUniversity of Southern DenmarkBiomolecular Nanoscale Engineering Center (BioNEC)Denmark

Hans‐Achim WagenknechtKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Fuan WangInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Christian WellnerKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Itamar WillnerInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Kazushige YamanaDepartment of Materials Science and ChemistryUniversity of HyogoHimeji Japan

Notably one of the most influential scientific achievements of the last century concerns the structural elucidation of DNA by Watson Crick Franklin and Wilkins in 1953 [1] As was foreseen in their seminal papers the structure of DNA had profound implications on molecular biology

ldquoWe wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA) This structure has novel features which are of considerable biological interestrdquo

Since then the role of DNA in biology has been accepted as that of the bearer of the genetic code and many genomic sequences have been deciphered including the human genome However the story is far from over and many questions still remain to be answered in particular the details of how DNA works to fulfil its duties including the sequence dependent local structure protein binding to DNA regulation of gene expression (including methylation and selective unwinding from histones) to name but a few Also although knowledge of the three‐letter genetic code allows for the identification of genes and comparison between species to find similarities and heritage it also raises the question of the exact role of the non‐ coding regions of the genomes

Not long after the huge biological importance of DNA had been understood the fascinating features of this self‐assembled biopolymer began to inspire synthetic chemists analytical specialists biophysicists and even computer programmers to devote their research efforts to oligonucleotide‐based systems

The basic principle of the workings of DNA is simple the molecule forms a well‐understood double helix through the complementary base pairing of two antiparallel strands Yet there is far more to DNA than just this concept DNA can act both as a rigid stick (duplex) with a persistence length of about 40ndash50 nm and as a flexible glue (single strand) giving rise to a Lego‐like building block system for the creation of architectures with nanometre precision In addition more complex tertiary structures such as loops triple strands quadru-plexes and various junctions many of which have been found in vivo add to the countless possibilities of creating DNA structures with functions beyond those of just information storage and heredity The plethora of non‐duplex tertiary structures is even more pronounced in the RNA context

By taking DNA out of its biological environment new systems have emerged that are beginning to play a major role in materials science electronics diagnostics medicinal chemistry and much more The supramo-lecular aspects of DNA have seen significant advances in the past few decades particularly with the inclusion of modified nucleotides

Organic synthesis has and will remain a key aspect of DNA chemistry The concept of phosphoramidite chemistry for automated solid‐phase synthesis (SPS) of DNA as first described by Caruthers in 1981 [2] has on the whole remained unaltered as it has proven to be a most versatile approach In principle any diol can

Preface

xx Preface

be used for the stepwise build‐up of functional molecules as the concept is not restricted to nucleosides provided the other functional groups that are present are compatible with the strongly acidic basic and oxidising environment in SPS although milder conditions are also available In addition nucleosides can be chemically functionalised with almost any additional group be it small organic molecules or large metal complexes The combination of all accessible building blocks has lead to a system that is now being explored in almost all areas of science as mentioned earlier

The chapters in this book present an excellent collection of state‐of‐the‐art reviews covering research that is currently being carried out The chapters are devoted to the most important fields being studied

1 (Non‐) covalently modified DNA with novel functions2 DNA wires and electron transport through DNA3 Oligonucleotides in sensing and diagnostic applications4 Conjugation of DNA with biomolecules and nanoparticles5 Alternative DNA structures switches and nanomachines

Each chapter is devoted to a specialised topic within the larger context of DNA chemistry and will give the reader both an introduction to the field and the relevant technologies and a more focussed description of the authorsrsquo own research and viewpoint General conclusions and outlooks for the future are also given We are in the very lucky position of having been able to attract many of the key players in the relevant areas to devote their time to writing what we believe is an outstanding collection of well written and up‐to‐date chapters As the field is growing so rapidly it would be beyond the scope of any textbook to include everyone currently working in this field or to mention the excellent new ideas of every research group This demonstrates that applied DNA technology has reached the level at which it is playing a key role across the board

Nucleotide technology is a fast moving area where research is advancing rapidly However these chapters will certainly remain a key collection for some years to come Even though the systems will steadily improve the basic technologies presented and discussed here will remain the same for the foreseeable future as can be seen from the basic SPS principles The book is intended to give the novice an introduction and a basic overview of all aspects of nucleotide technology including strategies concepts and visions The experienced reader will have an up‐to‐date volume at hand where ndash through the amalgamation of very different ideas ndash novel applications and concepts may be conceived We are therefore convinced that this collection will be very useful to scientists at all levels and we hope that it will indeed trigger the emergence of new research

It is generally difficult if not impossible to predict where the future will take us as new results are being published on a daily basis sometimes in unrelated fields where the impact on onersquos own research may not be immediately evident Many of the approaches used today could not have been predicted ten years ago as some of the key technologies were not available then (eg DNA origami) DNA technology will continue to be important at both the giving and receiving ends DNA bio-nanotechnology will influence material medicinal and biological sciences whereas inventions and demands from those fields will have an impact on the direction of the development of DNA technology

We give great thanks to all contributors to this book and hope that the reader will enjoy it as much as we did during the editorial stages

Eugen StulzGuido H Clever

Preface xxi

References

[1] (a) R E Franklin and R G Gosling Molecular configuration in sodium thymonucleate Nature 1953 171 (4356) 740ndash741 (b) J D Watson and F H C Crick Molecular structure of nucleic acids A structure for deoxyribose nucleic acid Nature 1953 171 (4356) 737ndash738 (c) M H Wilkins A R Stokes and H R Wilson Molecular structure of nucleic acids Molecular structure of deoxypentose nucleic acids Nature 1953 171 (4356) 738ndash740

[2] (a) S L Beaucage and M H Caruthers Deoxynucleoside phosphoramidites ndash A new class of key intermediates for deoxypolynucleotide synthesis Tetrahedron Lett 1981 22 (20) 1859ndash1862 (b) M D Matteucci and M H and Caruthers Nucleotide Chemistry 4 Synthesis of deoxyoligonucleotides on a polymer support J Am Chem Soc 1981 103 (11) 3185ndash3191

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

Contents vii

22 Electrical Conductance of DNA Oligomers mdash A Review of Experimental Results 94221 Introduction 94222 DNA structures 95223 Scanning probe microscopy 95

2231 STM break junction 962232 Conductive AFM 96

224 Lithographically defined junctions 982241 Mechanically controllable break junctions 982242 Direct contacts 992243 Carbon nanotube contacts 100

225 Conclusions 101References 102

23 DNA Sensors Using DNA Charge Transport Chemistry 105231 Introduction 105232 DNA‐functionalized electrochemical sensors 107

2321 Redox probes for ground state DNA‐mediated charge transport detection 1092322 Different platforms for DNA electrochemistry 1102323 Detection of single base mutations and DNA lesions 111

233 Detection of DNA‐binding proteins 1112331 Detection of transcriptional regulators 1112332 Methyltransferase and methylation detection 1122333 Photolyase activity and detection 1142334 ATP‐dependent XPD activity on surfaces 114

234 DNA CT within the cell 1152341 DNA CT can occur within biologically relevant environments 115

235 Conclusions 117Acknowledgements 117References 117

24 Charge Transfer in Non‐B DNA with a Tetraplex Structure 121241 Introduction 121242 CT in dsDNA (B‐DNA) 122243 CT in non‐B DNA with a tetraplex structure 123

2431 G‐quadruplex DNA 1232432 i‐motif DNA 127

244 Conclusions 132Acknowledgments 132References 132

Part III Oligonucleotides in Sensing and Diagnostic Applications 137

31 Development of Electrochemical Sensors for DNA Analysis 139311 Introduction 139312 Genosensors based on direct electrocactivity of nucleic bases 140313 Genosensors based on electrochemical mediators 141314 Genosensors based on free diffusional redox markers 142

viii Contents

315 Genosensors incorporating DNA probes modified with redox active molecules ndash lsquosignal‐offrsquo and lsquosignal‐onrsquo working modes 145

316 Genosensors for simultaneous detection of two different DNA targets 151317 Conclusions 154Acknowledgements 154References 154

32 Oligonucleotide Based Artificial Ribonucleases (OBANs) 158321 Introduction 158322 Early development of OBANs 159323 Metal ion based artificial nucleases 159324 Non‐metal ion based systems 161325 Creating bulges in the RNA substrate 162326 PNAzymes and creation of artificial RNA restriction enzymes 164327 Conclusions 167References 168

33 Exploring Nucleic Acid Conformations by Employment of Porphyrin Non‐covalent and Covalent Probes and Chiroptical Analysis 172

331 Introduction 172332 Non‐covalent interaction of porphyrinndashDNA complexes 174

3321 Interaction with single‐stranded DNA 1743322 Double helix conformations B‐ and Z‐DNA 1763323 G‐quadruplex 181

333 Porphyrins covalently linked to DNA 1873331 Porphyrins attached to 5prime‐ and 3prime‐termini of DNA with phosphates and amides 187

33311 5prime‐Phosphate linkage 18733312 Detection of the B‐ to Z‐transition 18933313 3prime‐Amide linkage 19133314 5prime‐Amide linkage 192

3332 Capping effect 1933333 Porphyrin C-nucleoside replacement of natural nucleobases 1973334 Porphyrins embedded in the backbone of DNA 1973335 Diastereochemically pure anionic porphyrinndashDNA dimers 1983336 Incorporation of rigid and flexible linked porphyrins to DNA nucleobases 200

334 Conclusions 203References 203

34 Chemical Reactions Controlled by Nucleic Acids and their Applications for Detection of Nucleic Acids in Live Cells 209

341 Introduction 209342 Intracellular nucleic acid targets 211343 Methods for monitoring ribonucleic acids in live cells 211

3431 Genetically encoded reporters 2123432 Hybridization‐responsive oligonucleotide probes 213

Contents ix

3433 Fluorogenic templated reactions 21434331 Nucleophilic substitution reactions 21434332 Staudinger reduction 216

3434 Photochemical reactions 221344 Perspectives 225References 226

35 The Biotechnological Applications of G‐Quartets 229351 Introduction 229352 Nucleobases and H‐bonds 229353 Duplex‐DNA mimics 231354 Guanine and G‐quartets 232355 G‐Quartets and G‐quadruplexes 232

3551 Colorimetric detection 2343552 Luminescencendashfluorescence detection 2343553 Electrochemical detection 235

356 Quadruplex‐DNA mimics 2363561 Intermolecular SQ G‐monomers 2363562 Intermolecular interconnected SQ G‐dimers 2393563 Intramolecular SQ (or iSQ) G‐tetramers 240

357 Conclusions 244References 244

Part IV Conjugation of DNA with Biomolecules and Nanoparticles 247

41 Nucleic Acid Controlled Reactions on Large Nucleic Acid Templates 249411 Introduction 249412 Nucleic acid controlled chemical reactions 250413 Applications 257

4131 Reactions on intracellular RNA 2574132 Reactions on large biogenic DNA and RNA templates in vitro 2594133 Drug screening 2624134 Materials science 266

414 Conclusions 268References 270

42 Lipid Oligonucleotide Bioconjugates Applications in Medicinal Chemistry 276421 Introduction 276422 Chemical approach to the synthesis of lipidndasholigonucleotide conjugates 277

4221 Solid‐phase (or pre‐synthetic) approach 27742211 Lipid conjugation at the 3ʹ‐terminal 27742212 Lipid conjugation at 5ʹ‐terminal 28042213 Lipid conjugation at internal position (intra‐chain) 282

4222 Solution‐phase (or post‐synthetic) approach 284

x Contents

423 Biomedical applications 2864231 LONs as efficient delivery vehicles in gene therapy 2864232 Other biomedical applications of LONs 288

424 Conclusions 288Acknowledgements 289References 289

43 Amphiphilic PeptidylndashRNA 294431 Introduction 294432 Three souls alas are dwelling in my breast [2] 295433 Why RNA Why peptides 296434 Hydrolysis‐resistant amphiphilic 3ʹ‐peptidylndashRNA 297435 Synthetic strategy 299436 Prosrsquon cons 300437 Alternative methods and strategies 302438 Molecular properties 302439 Supramolecular properties 3024310 Conclusions and perspectives 304Acknowledgements 306References 306

44 Oligonucleotide‐Stabilized Silver Nanoclusters 308441 Introduction 308442 Sensors 311

4421 Metallic sensors 3114422 Small molecule sensors 3124423 Protein sensors 3134424 Nucleic acid sensors 316

44241 DNA sensors 31744242 MiRNAs sensors 319

4425 Cells 320443 DNA computing (logic gates) 321444 Assorted examples 322445 Conclusions 323References 323

Part V Alternative DNA Structures Switches and Nanomachines 329

51 Structure and Stabilization of CGC+ Triplex DNA 331511 Introduction 331512 Classification of DNA triplets 332513 Structure of triplexes 332514 Triplex stabilizing factors 334

5141 Effect of pH on the triplex 3355142 Effect of cations on the triplex 3355143 Effect of length and composition of the three strands on the triplex 3365144 Molecular crowding 337

Contents xi

515 Formation of stable CGC+ triplex DNA 3375151 Analogues mimicking protonated cytosine 3375152 Analogues with increased pK

a 339

5153 Backbone modification 3405154 Triplex binding ligands 3415155 Other stabilizing effects 344

51551 Polyamines 34451552 Basic oligopeptides 34451553 Silver ions and silver nanoclusters 34551554 Single‐walled carbon nanotubes 346

516 Summary 346References 346

52 Synthetic Molecules as Guides for DNA Nanostructure Formation 353521 Introduction 353522 Covalent insertion of synthetic molecules into DNA 353

5221 Incorporating organic molecules into DNA 3545222 Adjusting flexibility 354

52221 Mediating DNA self‐assembly 3555223 Direct effect of synthetic organic linkers on DNA stability and assembly 357

52231 Supramolecular assembly guided through synthetic additions to DNA 35952232 Backbone insertion of metal binding organic molecules 359

523 Non‐covalently guided DNA assembly 3645231 DNA intercalators 3645232 Groove binding 367

524 Conclusions 369References 369

53 DNA‐Based Nanostructuring with Branched Oligonucleotide Hybrids 375531 Introduction 375532 Branched oligonucleotides 377533 Hybrids with rigid cores 378534 Second‐generation hybrids with a rigid core 382535 Solution‐phase syntheses Synthetic challenges 385536 Hybrid materials 389537 Outlook 392538 Conclusions 394Acknowledgements 394References 394

54 DNA‐Controlled Assembly of Soft Nanoparticles 397541 Introduction 397542 Sequence design 399

5421 Double membrane anchor ssDNA design 3995422 Single membrane anchor multiple ssDNA design 3995423 Single membrane anchor multiple ssDNA design for irreversible

assembly (fusionhemifusion) 400

xii Contents

543 Lipid membrane anchors 400544 DNA‐controlled assembly studied by UV spectroscopy 402

5441 Thermal stability of lipid‐modified DNA conjugates 4045442 DNA mismatch discrimination studies 405

545 Assembly on solid support 406546 Assembly of giant unilamellar liposomes (GUVs) 408547 Conclusions 409Acknowledgements 409References 409

55 Metal Ions in Ribozymes and Riboswitches 412551 Introduction 412552 Coordination chemistry of RNA 413553 Ribozymes 415

5531 Overview of the ribozyme world 4155532 Small ribozymes 4155533 Large ribozymes 417

554 Riboswitches 4205541 Overview of the riboswitch world 4205542 Metal ions assisting riboswitch folding and ligand recognition 4225543 Riboswitch ligands containing a metal 423

55431 Mg2+‐sensing riboswitches 42355432 B

12‐riboswitches 424

55433 MoCoTuCo‐riboswitches 425555 Summary 425Acknowledgement 426References 426

56 DNA Switches and Machines 434561 Introduction 434562 Ion‐stimulated and photonicelectrical‐triggered DNA switches 438

5621 Ion‐stimulated DNA switches 4385622 Photonic and electrical triggering of DNA switches 443

563 Switchable DNA machines 4475631 Two‐state switchable DNA machines 4485632 Multi‐state DNA machines 455

564 Applications of DNA switches and machines 459565 Conclusions and perspectives 466References 467

57 DNA‐Based Asymmetric Catalysis 474571 Introduction 474572 Concept of DNA‐based asymmetric catalysis 474573 Design approaches in DNA‐based asymmetric catalysis 475574 Covalent anchoring 476

Contents xiii

575 Supramolecular anchoring 4785751 First generation DNA‐based catalysts 4785752 Improvement of the catalytic system ndash second generation catalysts 4785753 Catalytic scope of DNA‐based catalysts 479

57531 Conjugated addition reactions 48057532 Miscellaneous reactions 483

5754 Mechanistic studies and role of DNA in catalysis 48457541 DielsndashAlder cycloaddition 48557542 FriedelndashCrafts reaction 48657543 Michael addition 48657544 Hydration of enones 48757545 Stereochemistry in DNA‐based catalytic asymmetric reactions 487

576 Conclusions and perspectives 488References 489

Index 491

Philippe BartheacuteleacutemyUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Jacqueline K BartonDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Nina BerovaDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

Glenn A BurleyDepartment of Pure and Applied ChemistryUniversity of StrathclydeGlasgow UK

Niklaas J BuurmaPhysical Organic Chemistry CentreSchool of ChemistryCardiff UniversityCardiff UK

Jungkweon ChoiThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Jean‐Louis DupreyGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Alessandro DrsquoUrsoDepartment of ScienceUniversity of CataniaCatania Sicily Italy

George A EllestadDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

A ErbeHelmholtz‐Zentrum Dresden‐RossendorfInstitute of Ion Beam Physics and Materials ResearchDivision Scaling PhenomenaDresden Germany

Maria Elena FragalagraveDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Ariel L FurstDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

List of Contributors

xvi List of Contributors

Sofia GalloDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alice GhidiniKarolinska InstituteDepartment of Biosciences and NutritionNovum Sweden

Arnaud GissotUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Andrea GreschnerDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Helmut GriesserInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Michael A GrodickDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Anika KernDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

Alfonso LatorreInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Chun‐Hua LuInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Tetsuro MajimaThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Andriy MokhirFriedrich‐Alexander‐University Erlangen‐NuumlrnbergDepartment of Chemistry and PharmacyGermany

David MonchaudICMUB (Institut de Chimie Moleculaire Universite de Bourgogne)CNRS UMR6302Dijon France

Jens MuumlllerInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Merita MurtolaKarolinska InstituteDepartment of Biosciences and NutritionNovum Swedenand Department of ChemistryUniversity of TurkuTurku Finland

Anastasia MusiariDepartment of ChemistryUniversity of ZurichZurich Switzerland

List of Contributors xvii

Khalid OumzilUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Amit PatwaUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Ana G PetrovicDepartment of ChemistryColumbia UniversityHavemeyer Halland Department of Life SciencesNew York Institute of Technology (NYIT)New YorkNY USA

Fang PuLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Roberto PurrelloDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Hanna RadeckaDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jerzy RadeckiDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jinsong RenLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Clemens RichertInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Ana Rioz‐MartiacutenezStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Gerard RoelfesStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Fiora RosatiDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Magdalena Rowinska‐ZyrekDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alexander SchwengerInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Oliver SeitzDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

xviii List of Contributors

Mitsuhiko ShionoyaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Roland K O SigelDepartment of ChemistryUniversity of ZurichZurich Switzerland

Indranil SinhaInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Hanadi SleimanDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Aacutelvaro SomozaInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Peter StrazewskiInstitut de Chimie et Biochimie Moleacuteculaires et Supramoleacuteculaires (UMR 5246)Universiteacute de LyonLyon France

Roger StroumlmbergKarolinska InstituteDepartment of Biosciences and NutritionNovumSweden

Claudia StubinitzkyKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Yusuke TakezawaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Manuel A TamargoDepartment of ChemistryColumbia UniversityHavemeyer HallNew York NYUSA

Stefan VogelDepartment of PhysicsChemistry and PharmacyUniversity of Southern DenmarkBiomolecular Nanoscale Engineering Center (BioNEC)Denmark

Hans‐Achim WagenknechtKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Fuan WangInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Christian WellnerKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Itamar WillnerInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Kazushige YamanaDepartment of Materials Science and ChemistryUniversity of HyogoHimeji Japan

Notably one of the most influential scientific achievements of the last century concerns the structural elucidation of DNA by Watson Crick Franklin and Wilkins in 1953 [1] As was foreseen in their seminal papers the structure of DNA had profound implications on molecular biology

ldquoWe wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA) This structure has novel features which are of considerable biological interestrdquo

Since then the role of DNA in biology has been accepted as that of the bearer of the genetic code and many genomic sequences have been deciphered including the human genome However the story is far from over and many questions still remain to be answered in particular the details of how DNA works to fulfil its duties including the sequence dependent local structure protein binding to DNA regulation of gene expression (including methylation and selective unwinding from histones) to name but a few Also although knowledge of the three‐letter genetic code allows for the identification of genes and comparison between species to find similarities and heritage it also raises the question of the exact role of the non‐ coding regions of the genomes

Not long after the huge biological importance of DNA had been understood the fascinating features of this self‐assembled biopolymer began to inspire synthetic chemists analytical specialists biophysicists and even computer programmers to devote their research efforts to oligonucleotide‐based systems

The basic principle of the workings of DNA is simple the molecule forms a well‐understood double helix through the complementary base pairing of two antiparallel strands Yet there is far more to DNA than just this concept DNA can act both as a rigid stick (duplex) with a persistence length of about 40ndash50 nm and as a flexible glue (single strand) giving rise to a Lego‐like building block system for the creation of architectures with nanometre precision In addition more complex tertiary structures such as loops triple strands quadru-plexes and various junctions many of which have been found in vivo add to the countless possibilities of creating DNA structures with functions beyond those of just information storage and heredity The plethora of non‐duplex tertiary structures is even more pronounced in the RNA context

By taking DNA out of its biological environment new systems have emerged that are beginning to play a major role in materials science electronics diagnostics medicinal chemistry and much more The supramo-lecular aspects of DNA have seen significant advances in the past few decades particularly with the inclusion of modified nucleotides

Organic synthesis has and will remain a key aspect of DNA chemistry The concept of phosphoramidite chemistry for automated solid‐phase synthesis (SPS) of DNA as first described by Caruthers in 1981 [2] has on the whole remained unaltered as it has proven to be a most versatile approach In principle any diol can

Preface

xx Preface

be used for the stepwise build‐up of functional molecules as the concept is not restricted to nucleosides provided the other functional groups that are present are compatible with the strongly acidic basic and oxidising environment in SPS although milder conditions are also available In addition nucleosides can be chemically functionalised with almost any additional group be it small organic molecules or large metal complexes The combination of all accessible building blocks has lead to a system that is now being explored in almost all areas of science as mentioned earlier

The chapters in this book present an excellent collection of state‐of‐the‐art reviews covering research that is currently being carried out The chapters are devoted to the most important fields being studied

1 (Non‐) covalently modified DNA with novel functions2 DNA wires and electron transport through DNA3 Oligonucleotides in sensing and diagnostic applications4 Conjugation of DNA with biomolecules and nanoparticles5 Alternative DNA structures switches and nanomachines

Each chapter is devoted to a specialised topic within the larger context of DNA chemistry and will give the reader both an introduction to the field and the relevant technologies and a more focussed description of the authorsrsquo own research and viewpoint General conclusions and outlooks for the future are also given We are in the very lucky position of having been able to attract many of the key players in the relevant areas to devote their time to writing what we believe is an outstanding collection of well written and up‐to‐date chapters As the field is growing so rapidly it would be beyond the scope of any textbook to include everyone currently working in this field or to mention the excellent new ideas of every research group This demonstrates that applied DNA technology has reached the level at which it is playing a key role across the board

Nucleotide technology is a fast moving area where research is advancing rapidly However these chapters will certainly remain a key collection for some years to come Even though the systems will steadily improve the basic technologies presented and discussed here will remain the same for the foreseeable future as can be seen from the basic SPS principles The book is intended to give the novice an introduction and a basic overview of all aspects of nucleotide technology including strategies concepts and visions The experienced reader will have an up‐to‐date volume at hand where ndash through the amalgamation of very different ideas ndash novel applications and concepts may be conceived We are therefore convinced that this collection will be very useful to scientists at all levels and we hope that it will indeed trigger the emergence of new research

It is generally difficult if not impossible to predict where the future will take us as new results are being published on a daily basis sometimes in unrelated fields where the impact on onersquos own research may not be immediately evident Many of the approaches used today could not have been predicted ten years ago as some of the key technologies were not available then (eg DNA origami) DNA technology will continue to be important at both the giving and receiving ends DNA bio-nanotechnology will influence material medicinal and biological sciences whereas inventions and demands from those fields will have an impact on the direction of the development of DNA technology

We give great thanks to all contributors to this book and hope that the reader will enjoy it as much as we did during the editorial stages

Eugen StulzGuido H Clever

Preface xxi

References

[1] (a) R E Franklin and R G Gosling Molecular configuration in sodium thymonucleate Nature 1953 171 (4356) 740ndash741 (b) J D Watson and F H C Crick Molecular structure of nucleic acids A structure for deoxyribose nucleic acid Nature 1953 171 (4356) 737ndash738 (c) M H Wilkins A R Stokes and H R Wilson Molecular structure of nucleic acids Molecular structure of deoxypentose nucleic acids Nature 1953 171 (4356) 738ndash740

[2] (a) S L Beaucage and M H Caruthers Deoxynucleoside phosphoramidites ndash A new class of key intermediates for deoxypolynucleotide synthesis Tetrahedron Lett 1981 22 (20) 1859ndash1862 (b) M D Matteucci and M H and Caruthers Nucleotide Chemistry 4 Synthesis of deoxyoligonucleotides on a polymer support J Am Chem Soc 1981 103 (11) 3185ndash3191

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

viii Contents

315 Genosensors incorporating DNA probes modified with redox active molecules ndash lsquosignal‐offrsquo and lsquosignal‐onrsquo working modes 145

316 Genosensors for simultaneous detection of two different DNA targets 151317 Conclusions 154Acknowledgements 154References 154

32 Oligonucleotide Based Artificial Ribonucleases (OBANs) 158321 Introduction 158322 Early development of OBANs 159323 Metal ion based artificial nucleases 159324 Non‐metal ion based systems 161325 Creating bulges in the RNA substrate 162326 PNAzymes and creation of artificial RNA restriction enzymes 164327 Conclusions 167References 168

33 Exploring Nucleic Acid Conformations by Employment of Porphyrin Non‐covalent and Covalent Probes and Chiroptical Analysis 172

331 Introduction 172332 Non‐covalent interaction of porphyrinndashDNA complexes 174

3321 Interaction with single‐stranded DNA 1743322 Double helix conformations B‐ and Z‐DNA 1763323 G‐quadruplex 181

333 Porphyrins covalently linked to DNA 1873331 Porphyrins attached to 5prime‐ and 3prime‐termini of DNA with phosphates and amides 187

33311 5prime‐Phosphate linkage 18733312 Detection of the B‐ to Z‐transition 18933313 3prime‐Amide linkage 19133314 5prime‐Amide linkage 192

3332 Capping effect 1933333 Porphyrin C-nucleoside replacement of natural nucleobases 1973334 Porphyrins embedded in the backbone of DNA 1973335 Diastereochemically pure anionic porphyrinndashDNA dimers 1983336 Incorporation of rigid and flexible linked porphyrins to DNA nucleobases 200

334 Conclusions 203References 203

34 Chemical Reactions Controlled by Nucleic Acids and their Applications for Detection of Nucleic Acids in Live Cells 209

341 Introduction 209342 Intracellular nucleic acid targets 211343 Methods for monitoring ribonucleic acids in live cells 211

3431 Genetically encoded reporters 2123432 Hybridization‐responsive oligonucleotide probes 213

Contents ix

3433 Fluorogenic templated reactions 21434331 Nucleophilic substitution reactions 21434332 Staudinger reduction 216

3434 Photochemical reactions 221344 Perspectives 225References 226

35 The Biotechnological Applications of G‐Quartets 229351 Introduction 229352 Nucleobases and H‐bonds 229353 Duplex‐DNA mimics 231354 Guanine and G‐quartets 232355 G‐Quartets and G‐quadruplexes 232

3551 Colorimetric detection 2343552 Luminescencendashfluorescence detection 2343553 Electrochemical detection 235

356 Quadruplex‐DNA mimics 2363561 Intermolecular SQ G‐monomers 2363562 Intermolecular interconnected SQ G‐dimers 2393563 Intramolecular SQ (or iSQ) G‐tetramers 240

357 Conclusions 244References 244

Part IV Conjugation of DNA with Biomolecules and Nanoparticles 247

41 Nucleic Acid Controlled Reactions on Large Nucleic Acid Templates 249411 Introduction 249412 Nucleic acid controlled chemical reactions 250413 Applications 257

4131 Reactions on intracellular RNA 2574132 Reactions on large biogenic DNA and RNA templates in vitro 2594133 Drug screening 2624134 Materials science 266

414 Conclusions 268References 270

42 Lipid Oligonucleotide Bioconjugates Applications in Medicinal Chemistry 276421 Introduction 276422 Chemical approach to the synthesis of lipidndasholigonucleotide conjugates 277

4221 Solid‐phase (or pre‐synthetic) approach 27742211 Lipid conjugation at the 3ʹ‐terminal 27742212 Lipid conjugation at 5ʹ‐terminal 28042213 Lipid conjugation at internal position (intra‐chain) 282

4222 Solution‐phase (or post‐synthetic) approach 284

x Contents

423 Biomedical applications 2864231 LONs as efficient delivery vehicles in gene therapy 2864232 Other biomedical applications of LONs 288

424 Conclusions 288Acknowledgements 289References 289

43 Amphiphilic PeptidylndashRNA 294431 Introduction 294432 Three souls alas are dwelling in my breast [2] 295433 Why RNA Why peptides 296434 Hydrolysis‐resistant amphiphilic 3ʹ‐peptidylndashRNA 297435 Synthetic strategy 299436 Prosrsquon cons 300437 Alternative methods and strategies 302438 Molecular properties 302439 Supramolecular properties 3024310 Conclusions and perspectives 304Acknowledgements 306References 306

44 Oligonucleotide‐Stabilized Silver Nanoclusters 308441 Introduction 308442 Sensors 311

4421 Metallic sensors 3114422 Small molecule sensors 3124423 Protein sensors 3134424 Nucleic acid sensors 316

44241 DNA sensors 31744242 MiRNAs sensors 319

4425 Cells 320443 DNA computing (logic gates) 321444 Assorted examples 322445 Conclusions 323References 323

Part V Alternative DNA Structures Switches and Nanomachines 329

51 Structure and Stabilization of CGC+ Triplex DNA 331511 Introduction 331512 Classification of DNA triplets 332513 Structure of triplexes 332514 Triplex stabilizing factors 334

5141 Effect of pH on the triplex 3355142 Effect of cations on the triplex 3355143 Effect of length and composition of the three strands on the triplex 3365144 Molecular crowding 337

Contents xi

515 Formation of stable CGC+ triplex DNA 3375151 Analogues mimicking protonated cytosine 3375152 Analogues with increased pK

a 339

5153 Backbone modification 3405154 Triplex binding ligands 3415155 Other stabilizing effects 344

51551 Polyamines 34451552 Basic oligopeptides 34451553 Silver ions and silver nanoclusters 34551554 Single‐walled carbon nanotubes 346

516 Summary 346References 346

52 Synthetic Molecules as Guides for DNA Nanostructure Formation 353521 Introduction 353522 Covalent insertion of synthetic molecules into DNA 353

5221 Incorporating organic molecules into DNA 3545222 Adjusting flexibility 354

52221 Mediating DNA self‐assembly 3555223 Direct effect of synthetic organic linkers on DNA stability and assembly 357

52231 Supramolecular assembly guided through synthetic additions to DNA 35952232 Backbone insertion of metal binding organic molecules 359

523 Non‐covalently guided DNA assembly 3645231 DNA intercalators 3645232 Groove binding 367

524 Conclusions 369References 369

53 DNA‐Based Nanostructuring with Branched Oligonucleotide Hybrids 375531 Introduction 375532 Branched oligonucleotides 377533 Hybrids with rigid cores 378534 Second‐generation hybrids with a rigid core 382535 Solution‐phase syntheses Synthetic challenges 385536 Hybrid materials 389537 Outlook 392538 Conclusions 394Acknowledgements 394References 394

54 DNA‐Controlled Assembly of Soft Nanoparticles 397541 Introduction 397542 Sequence design 399

5421 Double membrane anchor ssDNA design 3995422 Single membrane anchor multiple ssDNA design 3995423 Single membrane anchor multiple ssDNA design for irreversible

assembly (fusionhemifusion) 400

xii Contents

543 Lipid membrane anchors 400544 DNA‐controlled assembly studied by UV spectroscopy 402

5441 Thermal stability of lipid‐modified DNA conjugates 4045442 DNA mismatch discrimination studies 405

545 Assembly on solid support 406546 Assembly of giant unilamellar liposomes (GUVs) 408547 Conclusions 409Acknowledgements 409References 409

55 Metal Ions in Ribozymes and Riboswitches 412551 Introduction 412552 Coordination chemistry of RNA 413553 Ribozymes 415

5531 Overview of the ribozyme world 4155532 Small ribozymes 4155533 Large ribozymes 417

554 Riboswitches 4205541 Overview of the riboswitch world 4205542 Metal ions assisting riboswitch folding and ligand recognition 4225543 Riboswitch ligands containing a metal 423

55431 Mg2+‐sensing riboswitches 42355432 B

12‐riboswitches 424

55433 MoCoTuCo‐riboswitches 425555 Summary 425Acknowledgement 426References 426

56 DNA Switches and Machines 434561 Introduction 434562 Ion‐stimulated and photonicelectrical‐triggered DNA switches 438

5621 Ion‐stimulated DNA switches 4385622 Photonic and electrical triggering of DNA switches 443

563 Switchable DNA machines 4475631 Two‐state switchable DNA machines 4485632 Multi‐state DNA machines 455

564 Applications of DNA switches and machines 459565 Conclusions and perspectives 466References 467

57 DNA‐Based Asymmetric Catalysis 474571 Introduction 474572 Concept of DNA‐based asymmetric catalysis 474573 Design approaches in DNA‐based asymmetric catalysis 475574 Covalent anchoring 476

Contents xiii

575 Supramolecular anchoring 4785751 First generation DNA‐based catalysts 4785752 Improvement of the catalytic system ndash second generation catalysts 4785753 Catalytic scope of DNA‐based catalysts 479

57531 Conjugated addition reactions 48057532 Miscellaneous reactions 483

5754 Mechanistic studies and role of DNA in catalysis 48457541 DielsndashAlder cycloaddition 48557542 FriedelndashCrafts reaction 48657543 Michael addition 48657544 Hydration of enones 48757545 Stereochemistry in DNA‐based catalytic asymmetric reactions 487

576 Conclusions and perspectives 488References 489

Index 491

Philippe BartheacuteleacutemyUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Jacqueline K BartonDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Nina BerovaDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

Glenn A BurleyDepartment of Pure and Applied ChemistryUniversity of StrathclydeGlasgow UK

Niklaas J BuurmaPhysical Organic Chemistry CentreSchool of ChemistryCardiff UniversityCardiff UK

Jungkweon ChoiThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Jean‐Louis DupreyGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Alessandro DrsquoUrsoDepartment of ScienceUniversity of CataniaCatania Sicily Italy

George A EllestadDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

A ErbeHelmholtz‐Zentrum Dresden‐RossendorfInstitute of Ion Beam Physics and Materials ResearchDivision Scaling PhenomenaDresden Germany

Maria Elena FragalagraveDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Ariel L FurstDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

List of Contributors

xvi List of Contributors

Sofia GalloDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alice GhidiniKarolinska InstituteDepartment of Biosciences and NutritionNovum Sweden

Arnaud GissotUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Andrea GreschnerDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Helmut GriesserInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Michael A GrodickDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Anika KernDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

Alfonso LatorreInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Chun‐Hua LuInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Tetsuro MajimaThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Andriy MokhirFriedrich‐Alexander‐University Erlangen‐NuumlrnbergDepartment of Chemistry and PharmacyGermany

David MonchaudICMUB (Institut de Chimie Moleculaire Universite de Bourgogne)CNRS UMR6302Dijon France

Jens MuumlllerInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Merita MurtolaKarolinska InstituteDepartment of Biosciences and NutritionNovum Swedenand Department of ChemistryUniversity of TurkuTurku Finland

Anastasia MusiariDepartment of ChemistryUniversity of ZurichZurich Switzerland

List of Contributors xvii

Khalid OumzilUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Amit PatwaUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Ana G PetrovicDepartment of ChemistryColumbia UniversityHavemeyer Halland Department of Life SciencesNew York Institute of Technology (NYIT)New YorkNY USA

Fang PuLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Roberto PurrelloDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Hanna RadeckaDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jerzy RadeckiDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jinsong RenLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Clemens RichertInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Ana Rioz‐MartiacutenezStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Gerard RoelfesStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Fiora RosatiDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Magdalena Rowinska‐ZyrekDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alexander SchwengerInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Oliver SeitzDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

xviii List of Contributors

Mitsuhiko ShionoyaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Roland K O SigelDepartment of ChemistryUniversity of ZurichZurich Switzerland

Indranil SinhaInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Hanadi SleimanDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Aacutelvaro SomozaInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Peter StrazewskiInstitut de Chimie et Biochimie Moleacuteculaires et Supramoleacuteculaires (UMR 5246)Universiteacute de LyonLyon France

Roger StroumlmbergKarolinska InstituteDepartment of Biosciences and NutritionNovumSweden

Claudia StubinitzkyKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Yusuke TakezawaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Manuel A TamargoDepartment of ChemistryColumbia UniversityHavemeyer HallNew York NYUSA

Stefan VogelDepartment of PhysicsChemistry and PharmacyUniversity of Southern DenmarkBiomolecular Nanoscale Engineering Center (BioNEC)Denmark

Hans‐Achim WagenknechtKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Fuan WangInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Christian WellnerKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Itamar WillnerInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Kazushige YamanaDepartment of Materials Science and ChemistryUniversity of HyogoHimeji Japan

Notably one of the most influential scientific achievements of the last century concerns the structural elucidation of DNA by Watson Crick Franklin and Wilkins in 1953 [1] As was foreseen in their seminal papers the structure of DNA had profound implications on molecular biology

ldquoWe wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA) This structure has novel features which are of considerable biological interestrdquo

Since then the role of DNA in biology has been accepted as that of the bearer of the genetic code and many genomic sequences have been deciphered including the human genome However the story is far from over and many questions still remain to be answered in particular the details of how DNA works to fulfil its duties including the sequence dependent local structure protein binding to DNA regulation of gene expression (including methylation and selective unwinding from histones) to name but a few Also although knowledge of the three‐letter genetic code allows for the identification of genes and comparison between species to find similarities and heritage it also raises the question of the exact role of the non‐ coding regions of the genomes

Not long after the huge biological importance of DNA had been understood the fascinating features of this self‐assembled biopolymer began to inspire synthetic chemists analytical specialists biophysicists and even computer programmers to devote their research efforts to oligonucleotide‐based systems

The basic principle of the workings of DNA is simple the molecule forms a well‐understood double helix through the complementary base pairing of two antiparallel strands Yet there is far more to DNA than just this concept DNA can act both as a rigid stick (duplex) with a persistence length of about 40ndash50 nm and as a flexible glue (single strand) giving rise to a Lego‐like building block system for the creation of architectures with nanometre precision In addition more complex tertiary structures such as loops triple strands quadru-plexes and various junctions many of which have been found in vivo add to the countless possibilities of creating DNA structures with functions beyond those of just information storage and heredity The plethora of non‐duplex tertiary structures is even more pronounced in the RNA context

By taking DNA out of its biological environment new systems have emerged that are beginning to play a major role in materials science electronics diagnostics medicinal chemistry and much more The supramo-lecular aspects of DNA have seen significant advances in the past few decades particularly with the inclusion of modified nucleotides

Organic synthesis has and will remain a key aspect of DNA chemistry The concept of phosphoramidite chemistry for automated solid‐phase synthesis (SPS) of DNA as first described by Caruthers in 1981 [2] has on the whole remained unaltered as it has proven to be a most versatile approach In principle any diol can

Preface

xx Preface

be used for the stepwise build‐up of functional molecules as the concept is not restricted to nucleosides provided the other functional groups that are present are compatible with the strongly acidic basic and oxidising environment in SPS although milder conditions are also available In addition nucleosides can be chemically functionalised with almost any additional group be it small organic molecules or large metal complexes The combination of all accessible building blocks has lead to a system that is now being explored in almost all areas of science as mentioned earlier

The chapters in this book present an excellent collection of state‐of‐the‐art reviews covering research that is currently being carried out The chapters are devoted to the most important fields being studied

1 (Non‐) covalently modified DNA with novel functions2 DNA wires and electron transport through DNA3 Oligonucleotides in sensing and diagnostic applications4 Conjugation of DNA with biomolecules and nanoparticles5 Alternative DNA structures switches and nanomachines

Each chapter is devoted to a specialised topic within the larger context of DNA chemistry and will give the reader both an introduction to the field and the relevant technologies and a more focussed description of the authorsrsquo own research and viewpoint General conclusions and outlooks for the future are also given We are in the very lucky position of having been able to attract many of the key players in the relevant areas to devote their time to writing what we believe is an outstanding collection of well written and up‐to‐date chapters As the field is growing so rapidly it would be beyond the scope of any textbook to include everyone currently working in this field or to mention the excellent new ideas of every research group This demonstrates that applied DNA technology has reached the level at which it is playing a key role across the board

Nucleotide technology is a fast moving area where research is advancing rapidly However these chapters will certainly remain a key collection for some years to come Even though the systems will steadily improve the basic technologies presented and discussed here will remain the same for the foreseeable future as can be seen from the basic SPS principles The book is intended to give the novice an introduction and a basic overview of all aspects of nucleotide technology including strategies concepts and visions The experienced reader will have an up‐to‐date volume at hand where ndash through the amalgamation of very different ideas ndash novel applications and concepts may be conceived We are therefore convinced that this collection will be very useful to scientists at all levels and we hope that it will indeed trigger the emergence of new research

It is generally difficult if not impossible to predict where the future will take us as new results are being published on a daily basis sometimes in unrelated fields where the impact on onersquos own research may not be immediately evident Many of the approaches used today could not have been predicted ten years ago as some of the key technologies were not available then (eg DNA origami) DNA technology will continue to be important at both the giving and receiving ends DNA bio-nanotechnology will influence material medicinal and biological sciences whereas inventions and demands from those fields will have an impact on the direction of the development of DNA technology

We give great thanks to all contributors to this book and hope that the reader will enjoy it as much as we did during the editorial stages

Eugen StulzGuido H Clever

Preface xxi

References

[1] (a) R E Franklin and R G Gosling Molecular configuration in sodium thymonucleate Nature 1953 171 (4356) 740ndash741 (b) J D Watson and F H C Crick Molecular structure of nucleic acids A structure for deoxyribose nucleic acid Nature 1953 171 (4356) 737ndash738 (c) M H Wilkins A R Stokes and H R Wilson Molecular structure of nucleic acids Molecular structure of deoxypentose nucleic acids Nature 1953 171 (4356) 738ndash740

[2] (a) S L Beaucage and M H Caruthers Deoxynucleoside phosphoramidites ndash A new class of key intermediates for deoxypolynucleotide synthesis Tetrahedron Lett 1981 22 (20) 1859ndash1862 (b) M D Matteucci and M H and Caruthers Nucleotide Chemistry 4 Synthesis of deoxyoligonucleotides on a polymer support J Am Chem Soc 1981 103 (11) 3185ndash3191

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

Contents ix

3433 Fluorogenic templated reactions 21434331 Nucleophilic substitution reactions 21434332 Staudinger reduction 216

3434 Photochemical reactions 221344 Perspectives 225References 226

35 The Biotechnological Applications of G‐Quartets 229351 Introduction 229352 Nucleobases and H‐bonds 229353 Duplex‐DNA mimics 231354 Guanine and G‐quartets 232355 G‐Quartets and G‐quadruplexes 232

3551 Colorimetric detection 2343552 Luminescencendashfluorescence detection 2343553 Electrochemical detection 235

356 Quadruplex‐DNA mimics 2363561 Intermolecular SQ G‐monomers 2363562 Intermolecular interconnected SQ G‐dimers 2393563 Intramolecular SQ (or iSQ) G‐tetramers 240

357 Conclusions 244References 244

Part IV Conjugation of DNA with Biomolecules and Nanoparticles 247

41 Nucleic Acid Controlled Reactions on Large Nucleic Acid Templates 249411 Introduction 249412 Nucleic acid controlled chemical reactions 250413 Applications 257

4131 Reactions on intracellular RNA 2574132 Reactions on large biogenic DNA and RNA templates in vitro 2594133 Drug screening 2624134 Materials science 266

414 Conclusions 268References 270

42 Lipid Oligonucleotide Bioconjugates Applications in Medicinal Chemistry 276421 Introduction 276422 Chemical approach to the synthesis of lipidndasholigonucleotide conjugates 277

4221 Solid‐phase (or pre‐synthetic) approach 27742211 Lipid conjugation at the 3ʹ‐terminal 27742212 Lipid conjugation at 5ʹ‐terminal 28042213 Lipid conjugation at internal position (intra‐chain) 282

4222 Solution‐phase (or post‐synthetic) approach 284

x Contents

423 Biomedical applications 2864231 LONs as efficient delivery vehicles in gene therapy 2864232 Other biomedical applications of LONs 288

424 Conclusions 288Acknowledgements 289References 289

43 Amphiphilic PeptidylndashRNA 294431 Introduction 294432 Three souls alas are dwelling in my breast [2] 295433 Why RNA Why peptides 296434 Hydrolysis‐resistant amphiphilic 3ʹ‐peptidylndashRNA 297435 Synthetic strategy 299436 Prosrsquon cons 300437 Alternative methods and strategies 302438 Molecular properties 302439 Supramolecular properties 3024310 Conclusions and perspectives 304Acknowledgements 306References 306

44 Oligonucleotide‐Stabilized Silver Nanoclusters 308441 Introduction 308442 Sensors 311

4421 Metallic sensors 3114422 Small molecule sensors 3124423 Protein sensors 3134424 Nucleic acid sensors 316

44241 DNA sensors 31744242 MiRNAs sensors 319

4425 Cells 320443 DNA computing (logic gates) 321444 Assorted examples 322445 Conclusions 323References 323

Part V Alternative DNA Structures Switches and Nanomachines 329

51 Structure and Stabilization of CGC+ Triplex DNA 331511 Introduction 331512 Classification of DNA triplets 332513 Structure of triplexes 332514 Triplex stabilizing factors 334

5141 Effect of pH on the triplex 3355142 Effect of cations on the triplex 3355143 Effect of length and composition of the three strands on the triplex 3365144 Molecular crowding 337

Contents xi

515 Formation of stable CGC+ triplex DNA 3375151 Analogues mimicking protonated cytosine 3375152 Analogues with increased pK

a 339

5153 Backbone modification 3405154 Triplex binding ligands 3415155 Other stabilizing effects 344

51551 Polyamines 34451552 Basic oligopeptides 34451553 Silver ions and silver nanoclusters 34551554 Single‐walled carbon nanotubes 346

516 Summary 346References 346

52 Synthetic Molecules as Guides for DNA Nanostructure Formation 353521 Introduction 353522 Covalent insertion of synthetic molecules into DNA 353

5221 Incorporating organic molecules into DNA 3545222 Adjusting flexibility 354

52221 Mediating DNA self‐assembly 3555223 Direct effect of synthetic organic linkers on DNA stability and assembly 357

52231 Supramolecular assembly guided through synthetic additions to DNA 35952232 Backbone insertion of metal binding organic molecules 359

523 Non‐covalently guided DNA assembly 3645231 DNA intercalators 3645232 Groove binding 367

524 Conclusions 369References 369

53 DNA‐Based Nanostructuring with Branched Oligonucleotide Hybrids 375531 Introduction 375532 Branched oligonucleotides 377533 Hybrids with rigid cores 378534 Second‐generation hybrids with a rigid core 382535 Solution‐phase syntheses Synthetic challenges 385536 Hybrid materials 389537 Outlook 392538 Conclusions 394Acknowledgements 394References 394

54 DNA‐Controlled Assembly of Soft Nanoparticles 397541 Introduction 397542 Sequence design 399

5421 Double membrane anchor ssDNA design 3995422 Single membrane anchor multiple ssDNA design 3995423 Single membrane anchor multiple ssDNA design for irreversible

assembly (fusionhemifusion) 400

xii Contents

543 Lipid membrane anchors 400544 DNA‐controlled assembly studied by UV spectroscopy 402

5441 Thermal stability of lipid‐modified DNA conjugates 4045442 DNA mismatch discrimination studies 405

545 Assembly on solid support 406546 Assembly of giant unilamellar liposomes (GUVs) 408547 Conclusions 409Acknowledgements 409References 409

55 Metal Ions in Ribozymes and Riboswitches 412551 Introduction 412552 Coordination chemistry of RNA 413553 Ribozymes 415

5531 Overview of the ribozyme world 4155532 Small ribozymes 4155533 Large ribozymes 417

554 Riboswitches 4205541 Overview of the riboswitch world 4205542 Metal ions assisting riboswitch folding and ligand recognition 4225543 Riboswitch ligands containing a metal 423

55431 Mg2+‐sensing riboswitches 42355432 B

12‐riboswitches 424

55433 MoCoTuCo‐riboswitches 425555 Summary 425Acknowledgement 426References 426

56 DNA Switches and Machines 434561 Introduction 434562 Ion‐stimulated and photonicelectrical‐triggered DNA switches 438

5621 Ion‐stimulated DNA switches 4385622 Photonic and electrical triggering of DNA switches 443

563 Switchable DNA machines 4475631 Two‐state switchable DNA machines 4485632 Multi‐state DNA machines 455

564 Applications of DNA switches and machines 459565 Conclusions and perspectives 466References 467

57 DNA‐Based Asymmetric Catalysis 474571 Introduction 474572 Concept of DNA‐based asymmetric catalysis 474573 Design approaches in DNA‐based asymmetric catalysis 475574 Covalent anchoring 476

Contents xiii

575 Supramolecular anchoring 4785751 First generation DNA‐based catalysts 4785752 Improvement of the catalytic system ndash second generation catalysts 4785753 Catalytic scope of DNA‐based catalysts 479

57531 Conjugated addition reactions 48057532 Miscellaneous reactions 483

5754 Mechanistic studies and role of DNA in catalysis 48457541 DielsndashAlder cycloaddition 48557542 FriedelndashCrafts reaction 48657543 Michael addition 48657544 Hydration of enones 48757545 Stereochemistry in DNA‐based catalytic asymmetric reactions 487

576 Conclusions and perspectives 488References 489

Index 491

Philippe BartheacuteleacutemyUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Jacqueline K BartonDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Nina BerovaDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

Glenn A BurleyDepartment of Pure and Applied ChemistryUniversity of StrathclydeGlasgow UK

Niklaas J BuurmaPhysical Organic Chemistry CentreSchool of ChemistryCardiff UniversityCardiff UK

Jungkweon ChoiThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Jean‐Louis DupreyGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Alessandro DrsquoUrsoDepartment of ScienceUniversity of CataniaCatania Sicily Italy

George A EllestadDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

A ErbeHelmholtz‐Zentrum Dresden‐RossendorfInstitute of Ion Beam Physics and Materials ResearchDivision Scaling PhenomenaDresden Germany

Maria Elena FragalagraveDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Ariel L FurstDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

List of Contributors

xvi List of Contributors

Sofia GalloDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alice GhidiniKarolinska InstituteDepartment of Biosciences and NutritionNovum Sweden

Arnaud GissotUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Andrea GreschnerDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Helmut GriesserInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Michael A GrodickDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Anika KernDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

Alfonso LatorreInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Chun‐Hua LuInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Tetsuro MajimaThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Andriy MokhirFriedrich‐Alexander‐University Erlangen‐NuumlrnbergDepartment of Chemistry and PharmacyGermany

David MonchaudICMUB (Institut de Chimie Moleculaire Universite de Bourgogne)CNRS UMR6302Dijon France

Jens MuumlllerInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Merita MurtolaKarolinska InstituteDepartment of Biosciences and NutritionNovum Swedenand Department of ChemistryUniversity of TurkuTurku Finland

Anastasia MusiariDepartment of ChemistryUniversity of ZurichZurich Switzerland

List of Contributors xvii

Khalid OumzilUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Amit PatwaUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Ana G PetrovicDepartment of ChemistryColumbia UniversityHavemeyer Halland Department of Life SciencesNew York Institute of Technology (NYIT)New YorkNY USA

Fang PuLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Roberto PurrelloDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Hanna RadeckaDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jerzy RadeckiDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jinsong RenLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Clemens RichertInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Ana Rioz‐MartiacutenezStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Gerard RoelfesStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Fiora RosatiDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Magdalena Rowinska‐ZyrekDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alexander SchwengerInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Oliver SeitzDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

xviii List of Contributors

Mitsuhiko ShionoyaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Roland K O SigelDepartment of ChemistryUniversity of ZurichZurich Switzerland

Indranil SinhaInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Hanadi SleimanDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Aacutelvaro SomozaInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Peter StrazewskiInstitut de Chimie et Biochimie Moleacuteculaires et Supramoleacuteculaires (UMR 5246)Universiteacute de LyonLyon France

Roger StroumlmbergKarolinska InstituteDepartment of Biosciences and NutritionNovumSweden

Claudia StubinitzkyKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Yusuke TakezawaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Manuel A TamargoDepartment of ChemistryColumbia UniversityHavemeyer HallNew York NYUSA

Stefan VogelDepartment of PhysicsChemistry and PharmacyUniversity of Southern DenmarkBiomolecular Nanoscale Engineering Center (BioNEC)Denmark

Hans‐Achim WagenknechtKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Fuan WangInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Christian WellnerKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Itamar WillnerInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Kazushige YamanaDepartment of Materials Science and ChemistryUniversity of HyogoHimeji Japan

Notably one of the most influential scientific achievements of the last century concerns the structural elucidation of DNA by Watson Crick Franklin and Wilkins in 1953 [1] As was foreseen in their seminal papers the structure of DNA had profound implications on molecular biology

ldquoWe wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA) This structure has novel features which are of considerable biological interestrdquo

Since then the role of DNA in biology has been accepted as that of the bearer of the genetic code and many genomic sequences have been deciphered including the human genome However the story is far from over and many questions still remain to be answered in particular the details of how DNA works to fulfil its duties including the sequence dependent local structure protein binding to DNA regulation of gene expression (including methylation and selective unwinding from histones) to name but a few Also although knowledge of the three‐letter genetic code allows for the identification of genes and comparison between species to find similarities and heritage it also raises the question of the exact role of the non‐ coding regions of the genomes

Not long after the huge biological importance of DNA had been understood the fascinating features of this self‐assembled biopolymer began to inspire synthetic chemists analytical specialists biophysicists and even computer programmers to devote their research efforts to oligonucleotide‐based systems

The basic principle of the workings of DNA is simple the molecule forms a well‐understood double helix through the complementary base pairing of two antiparallel strands Yet there is far more to DNA than just this concept DNA can act both as a rigid stick (duplex) with a persistence length of about 40ndash50 nm and as a flexible glue (single strand) giving rise to a Lego‐like building block system for the creation of architectures with nanometre precision In addition more complex tertiary structures such as loops triple strands quadru-plexes and various junctions many of which have been found in vivo add to the countless possibilities of creating DNA structures with functions beyond those of just information storage and heredity The plethora of non‐duplex tertiary structures is even more pronounced in the RNA context

By taking DNA out of its biological environment new systems have emerged that are beginning to play a major role in materials science electronics diagnostics medicinal chemistry and much more The supramo-lecular aspects of DNA have seen significant advances in the past few decades particularly with the inclusion of modified nucleotides

Organic synthesis has and will remain a key aspect of DNA chemistry The concept of phosphoramidite chemistry for automated solid‐phase synthesis (SPS) of DNA as first described by Caruthers in 1981 [2] has on the whole remained unaltered as it has proven to be a most versatile approach In principle any diol can

Preface

xx Preface

be used for the stepwise build‐up of functional molecules as the concept is not restricted to nucleosides provided the other functional groups that are present are compatible with the strongly acidic basic and oxidising environment in SPS although milder conditions are also available In addition nucleosides can be chemically functionalised with almost any additional group be it small organic molecules or large metal complexes The combination of all accessible building blocks has lead to a system that is now being explored in almost all areas of science as mentioned earlier

The chapters in this book present an excellent collection of state‐of‐the‐art reviews covering research that is currently being carried out The chapters are devoted to the most important fields being studied

1 (Non‐) covalently modified DNA with novel functions2 DNA wires and electron transport through DNA3 Oligonucleotides in sensing and diagnostic applications4 Conjugation of DNA with biomolecules and nanoparticles5 Alternative DNA structures switches and nanomachines

Each chapter is devoted to a specialised topic within the larger context of DNA chemistry and will give the reader both an introduction to the field and the relevant technologies and a more focussed description of the authorsrsquo own research and viewpoint General conclusions and outlooks for the future are also given We are in the very lucky position of having been able to attract many of the key players in the relevant areas to devote their time to writing what we believe is an outstanding collection of well written and up‐to‐date chapters As the field is growing so rapidly it would be beyond the scope of any textbook to include everyone currently working in this field or to mention the excellent new ideas of every research group This demonstrates that applied DNA technology has reached the level at which it is playing a key role across the board

Nucleotide technology is a fast moving area where research is advancing rapidly However these chapters will certainly remain a key collection for some years to come Even though the systems will steadily improve the basic technologies presented and discussed here will remain the same for the foreseeable future as can be seen from the basic SPS principles The book is intended to give the novice an introduction and a basic overview of all aspects of nucleotide technology including strategies concepts and visions The experienced reader will have an up‐to‐date volume at hand where ndash through the amalgamation of very different ideas ndash novel applications and concepts may be conceived We are therefore convinced that this collection will be very useful to scientists at all levels and we hope that it will indeed trigger the emergence of new research

It is generally difficult if not impossible to predict where the future will take us as new results are being published on a daily basis sometimes in unrelated fields where the impact on onersquos own research may not be immediately evident Many of the approaches used today could not have been predicted ten years ago as some of the key technologies were not available then (eg DNA origami) DNA technology will continue to be important at both the giving and receiving ends DNA bio-nanotechnology will influence material medicinal and biological sciences whereas inventions and demands from those fields will have an impact on the direction of the development of DNA technology

We give great thanks to all contributors to this book and hope that the reader will enjoy it as much as we did during the editorial stages

Eugen StulzGuido H Clever

Preface xxi

References

[1] (a) R E Franklin and R G Gosling Molecular configuration in sodium thymonucleate Nature 1953 171 (4356) 740ndash741 (b) J D Watson and F H C Crick Molecular structure of nucleic acids A structure for deoxyribose nucleic acid Nature 1953 171 (4356) 737ndash738 (c) M H Wilkins A R Stokes and H R Wilson Molecular structure of nucleic acids Molecular structure of deoxypentose nucleic acids Nature 1953 171 (4356) 738ndash740

[2] (a) S L Beaucage and M H Caruthers Deoxynucleoside phosphoramidites ndash A new class of key intermediates for deoxypolynucleotide synthesis Tetrahedron Lett 1981 22 (20) 1859ndash1862 (b) M D Matteucci and M H and Caruthers Nucleotide Chemistry 4 Synthesis of deoxyoligonucleotides on a polymer support J Am Chem Soc 1981 103 (11) 3185ndash3191

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

x Contents

423 Biomedical applications 2864231 LONs as efficient delivery vehicles in gene therapy 2864232 Other biomedical applications of LONs 288

424 Conclusions 288Acknowledgements 289References 289

43 Amphiphilic PeptidylndashRNA 294431 Introduction 294432 Three souls alas are dwelling in my breast [2] 295433 Why RNA Why peptides 296434 Hydrolysis‐resistant amphiphilic 3ʹ‐peptidylndashRNA 297435 Synthetic strategy 299436 Prosrsquon cons 300437 Alternative methods and strategies 302438 Molecular properties 302439 Supramolecular properties 3024310 Conclusions and perspectives 304Acknowledgements 306References 306

44 Oligonucleotide‐Stabilized Silver Nanoclusters 308441 Introduction 308442 Sensors 311

4421 Metallic sensors 3114422 Small molecule sensors 3124423 Protein sensors 3134424 Nucleic acid sensors 316

44241 DNA sensors 31744242 MiRNAs sensors 319

4425 Cells 320443 DNA computing (logic gates) 321444 Assorted examples 322445 Conclusions 323References 323

Part V Alternative DNA Structures Switches and Nanomachines 329

51 Structure and Stabilization of CGC+ Triplex DNA 331511 Introduction 331512 Classification of DNA triplets 332513 Structure of triplexes 332514 Triplex stabilizing factors 334

5141 Effect of pH on the triplex 3355142 Effect of cations on the triplex 3355143 Effect of length and composition of the three strands on the triplex 3365144 Molecular crowding 337

Contents xi

515 Formation of stable CGC+ triplex DNA 3375151 Analogues mimicking protonated cytosine 3375152 Analogues with increased pK

a 339

5153 Backbone modification 3405154 Triplex binding ligands 3415155 Other stabilizing effects 344

51551 Polyamines 34451552 Basic oligopeptides 34451553 Silver ions and silver nanoclusters 34551554 Single‐walled carbon nanotubes 346

516 Summary 346References 346

52 Synthetic Molecules as Guides for DNA Nanostructure Formation 353521 Introduction 353522 Covalent insertion of synthetic molecules into DNA 353

5221 Incorporating organic molecules into DNA 3545222 Adjusting flexibility 354

52221 Mediating DNA self‐assembly 3555223 Direct effect of synthetic organic linkers on DNA stability and assembly 357

52231 Supramolecular assembly guided through synthetic additions to DNA 35952232 Backbone insertion of metal binding organic molecules 359

523 Non‐covalently guided DNA assembly 3645231 DNA intercalators 3645232 Groove binding 367

524 Conclusions 369References 369

53 DNA‐Based Nanostructuring with Branched Oligonucleotide Hybrids 375531 Introduction 375532 Branched oligonucleotides 377533 Hybrids with rigid cores 378534 Second‐generation hybrids with a rigid core 382535 Solution‐phase syntheses Synthetic challenges 385536 Hybrid materials 389537 Outlook 392538 Conclusions 394Acknowledgements 394References 394

54 DNA‐Controlled Assembly of Soft Nanoparticles 397541 Introduction 397542 Sequence design 399

5421 Double membrane anchor ssDNA design 3995422 Single membrane anchor multiple ssDNA design 3995423 Single membrane anchor multiple ssDNA design for irreversible

assembly (fusionhemifusion) 400

xii Contents

543 Lipid membrane anchors 400544 DNA‐controlled assembly studied by UV spectroscopy 402

5441 Thermal stability of lipid‐modified DNA conjugates 4045442 DNA mismatch discrimination studies 405

545 Assembly on solid support 406546 Assembly of giant unilamellar liposomes (GUVs) 408547 Conclusions 409Acknowledgements 409References 409

55 Metal Ions in Ribozymes and Riboswitches 412551 Introduction 412552 Coordination chemistry of RNA 413553 Ribozymes 415

5531 Overview of the ribozyme world 4155532 Small ribozymes 4155533 Large ribozymes 417

554 Riboswitches 4205541 Overview of the riboswitch world 4205542 Metal ions assisting riboswitch folding and ligand recognition 4225543 Riboswitch ligands containing a metal 423

55431 Mg2+‐sensing riboswitches 42355432 B

12‐riboswitches 424

55433 MoCoTuCo‐riboswitches 425555 Summary 425Acknowledgement 426References 426

56 DNA Switches and Machines 434561 Introduction 434562 Ion‐stimulated and photonicelectrical‐triggered DNA switches 438

5621 Ion‐stimulated DNA switches 4385622 Photonic and electrical triggering of DNA switches 443

563 Switchable DNA machines 4475631 Two‐state switchable DNA machines 4485632 Multi‐state DNA machines 455

564 Applications of DNA switches and machines 459565 Conclusions and perspectives 466References 467

57 DNA‐Based Asymmetric Catalysis 474571 Introduction 474572 Concept of DNA‐based asymmetric catalysis 474573 Design approaches in DNA‐based asymmetric catalysis 475574 Covalent anchoring 476

Contents xiii

575 Supramolecular anchoring 4785751 First generation DNA‐based catalysts 4785752 Improvement of the catalytic system ndash second generation catalysts 4785753 Catalytic scope of DNA‐based catalysts 479

57531 Conjugated addition reactions 48057532 Miscellaneous reactions 483

5754 Mechanistic studies and role of DNA in catalysis 48457541 DielsndashAlder cycloaddition 48557542 FriedelndashCrafts reaction 48657543 Michael addition 48657544 Hydration of enones 48757545 Stereochemistry in DNA‐based catalytic asymmetric reactions 487

576 Conclusions and perspectives 488References 489

Index 491

Philippe BartheacuteleacutemyUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Jacqueline K BartonDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Nina BerovaDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

Glenn A BurleyDepartment of Pure and Applied ChemistryUniversity of StrathclydeGlasgow UK

Niklaas J BuurmaPhysical Organic Chemistry CentreSchool of ChemistryCardiff UniversityCardiff UK

Jungkweon ChoiThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Jean‐Louis DupreyGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Alessandro DrsquoUrsoDepartment of ScienceUniversity of CataniaCatania Sicily Italy

George A EllestadDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

A ErbeHelmholtz‐Zentrum Dresden‐RossendorfInstitute of Ion Beam Physics and Materials ResearchDivision Scaling PhenomenaDresden Germany

Maria Elena FragalagraveDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Ariel L FurstDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

List of Contributors

xvi List of Contributors

Sofia GalloDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alice GhidiniKarolinska InstituteDepartment of Biosciences and NutritionNovum Sweden

Arnaud GissotUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Andrea GreschnerDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Helmut GriesserInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Michael A GrodickDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Anika KernDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

Alfonso LatorreInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Chun‐Hua LuInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Tetsuro MajimaThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Andriy MokhirFriedrich‐Alexander‐University Erlangen‐NuumlrnbergDepartment of Chemistry and PharmacyGermany

David MonchaudICMUB (Institut de Chimie Moleculaire Universite de Bourgogne)CNRS UMR6302Dijon France

Jens MuumlllerInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Merita MurtolaKarolinska InstituteDepartment of Biosciences and NutritionNovum Swedenand Department of ChemistryUniversity of TurkuTurku Finland

Anastasia MusiariDepartment of ChemistryUniversity of ZurichZurich Switzerland

List of Contributors xvii

Khalid OumzilUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Amit PatwaUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Ana G PetrovicDepartment of ChemistryColumbia UniversityHavemeyer Halland Department of Life SciencesNew York Institute of Technology (NYIT)New YorkNY USA

Fang PuLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Roberto PurrelloDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Hanna RadeckaDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jerzy RadeckiDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jinsong RenLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Clemens RichertInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Ana Rioz‐MartiacutenezStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Gerard RoelfesStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Fiora RosatiDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Magdalena Rowinska‐ZyrekDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alexander SchwengerInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Oliver SeitzDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

xviii List of Contributors

Mitsuhiko ShionoyaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Roland K O SigelDepartment of ChemistryUniversity of ZurichZurich Switzerland

Indranil SinhaInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Hanadi SleimanDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Aacutelvaro SomozaInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Peter StrazewskiInstitut de Chimie et Biochimie Moleacuteculaires et Supramoleacuteculaires (UMR 5246)Universiteacute de LyonLyon France

Roger StroumlmbergKarolinska InstituteDepartment of Biosciences and NutritionNovumSweden

Claudia StubinitzkyKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Yusuke TakezawaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Manuel A TamargoDepartment of ChemistryColumbia UniversityHavemeyer HallNew York NYUSA

Stefan VogelDepartment of PhysicsChemistry and PharmacyUniversity of Southern DenmarkBiomolecular Nanoscale Engineering Center (BioNEC)Denmark

Hans‐Achim WagenknechtKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Fuan WangInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Christian WellnerKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Itamar WillnerInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Kazushige YamanaDepartment of Materials Science and ChemistryUniversity of HyogoHimeji Japan

Notably one of the most influential scientific achievements of the last century concerns the structural elucidation of DNA by Watson Crick Franklin and Wilkins in 1953 [1] As was foreseen in their seminal papers the structure of DNA had profound implications on molecular biology

ldquoWe wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA) This structure has novel features which are of considerable biological interestrdquo

Since then the role of DNA in biology has been accepted as that of the bearer of the genetic code and many genomic sequences have been deciphered including the human genome However the story is far from over and many questions still remain to be answered in particular the details of how DNA works to fulfil its duties including the sequence dependent local structure protein binding to DNA regulation of gene expression (including methylation and selective unwinding from histones) to name but a few Also although knowledge of the three‐letter genetic code allows for the identification of genes and comparison between species to find similarities and heritage it also raises the question of the exact role of the non‐ coding regions of the genomes

Not long after the huge biological importance of DNA had been understood the fascinating features of this self‐assembled biopolymer began to inspire synthetic chemists analytical specialists biophysicists and even computer programmers to devote their research efforts to oligonucleotide‐based systems

The basic principle of the workings of DNA is simple the molecule forms a well‐understood double helix through the complementary base pairing of two antiparallel strands Yet there is far more to DNA than just this concept DNA can act both as a rigid stick (duplex) with a persistence length of about 40ndash50 nm and as a flexible glue (single strand) giving rise to a Lego‐like building block system for the creation of architectures with nanometre precision In addition more complex tertiary structures such as loops triple strands quadru-plexes and various junctions many of which have been found in vivo add to the countless possibilities of creating DNA structures with functions beyond those of just information storage and heredity The plethora of non‐duplex tertiary structures is even more pronounced in the RNA context

By taking DNA out of its biological environment new systems have emerged that are beginning to play a major role in materials science electronics diagnostics medicinal chemistry and much more The supramo-lecular aspects of DNA have seen significant advances in the past few decades particularly with the inclusion of modified nucleotides

Organic synthesis has and will remain a key aspect of DNA chemistry The concept of phosphoramidite chemistry for automated solid‐phase synthesis (SPS) of DNA as first described by Caruthers in 1981 [2] has on the whole remained unaltered as it has proven to be a most versatile approach In principle any diol can

Preface

xx Preface

be used for the stepwise build‐up of functional molecules as the concept is not restricted to nucleosides provided the other functional groups that are present are compatible with the strongly acidic basic and oxidising environment in SPS although milder conditions are also available In addition nucleosides can be chemically functionalised with almost any additional group be it small organic molecules or large metal complexes The combination of all accessible building blocks has lead to a system that is now being explored in almost all areas of science as mentioned earlier

The chapters in this book present an excellent collection of state‐of‐the‐art reviews covering research that is currently being carried out The chapters are devoted to the most important fields being studied

1 (Non‐) covalently modified DNA with novel functions2 DNA wires and electron transport through DNA3 Oligonucleotides in sensing and diagnostic applications4 Conjugation of DNA with biomolecules and nanoparticles5 Alternative DNA structures switches and nanomachines

Each chapter is devoted to a specialised topic within the larger context of DNA chemistry and will give the reader both an introduction to the field and the relevant technologies and a more focussed description of the authorsrsquo own research and viewpoint General conclusions and outlooks for the future are also given We are in the very lucky position of having been able to attract many of the key players in the relevant areas to devote their time to writing what we believe is an outstanding collection of well written and up‐to‐date chapters As the field is growing so rapidly it would be beyond the scope of any textbook to include everyone currently working in this field or to mention the excellent new ideas of every research group This demonstrates that applied DNA technology has reached the level at which it is playing a key role across the board

Nucleotide technology is a fast moving area where research is advancing rapidly However these chapters will certainly remain a key collection for some years to come Even though the systems will steadily improve the basic technologies presented and discussed here will remain the same for the foreseeable future as can be seen from the basic SPS principles The book is intended to give the novice an introduction and a basic overview of all aspects of nucleotide technology including strategies concepts and visions The experienced reader will have an up‐to‐date volume at hand where ndash through the amalgamation of very different ideas ndash novel applications and concepts may be conceived We are therefore convinced that this collection will be very useful to scientists at all levels and we hope that it will indeed trigger the emergence of new research

It is generally difficult if not impossible to predict where the future will take us as new results are being published on a daily basis sometimes in unrelated fields where the impact on onersquos own research may not be immediately evident Many of the approaches used today could not have been predicted ten years ago as some of the key technologies were not available then (eg DNA origami) DNA technology will continue to be important at both the giving and receiving ends DNA bio-nanotechnology will influence material medicinal and biological sciences whereas inventions and demands from those fields will have an impact on the direction of the development of DNA technology

We give great thanks to all contributors to this book and hope that the reader will enjoy it as much as we did during the editorial stages

Eugen StulzGuido H Clever

Preface xxi

References

[1] (a) R E Franklin and R G Gosling Molecular configuration in sodium thymonucleate Nature 1953 171 (4356) 740ndash741 (b) J D Watson and F H C Crick Molecular structure of nucleic acids A structure for deoxyribose nucleic acid Nature 1953 171 (4356) 737ndash738 (c) M H Wilkins A R Stokes and H R Wilson Molecular structure of nucleic acids Molecular structure of deoxypentose nucleic acids Nature 1953 171 (4356) 738ndash740

[2] (a) S L Beaucage and M H Caruthers Deoxynucleoside phosphoramidites ndash A new class of key intermediates for deoxypolynucleotide synthesis Tetrahedron Lett 1981 22 (20) 1859ndash1862 (b) M D Matteucci and M H and Caruthers Nucleotide Chemistry 4 Synthesis of deoxyoligonucleotides on a polymer support J Am Chem Soc 1981 103 (11) 3185ndash3191

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

Contents xi

515 Formation of stable CGC+ triplex DNA 3375151 Analogues mimicking protonated cytosine 3375152 Analogues with increased pK

a 339

5153 Backbone modification 3405154 Triplex binding ligands 3415155 Other stabilizing effects 344

51551 Polyamines 34451552 Basic oligopeptides 34451553 Silver ions and silver nanoclusters 34551554 Single‐walled carbon nanotubes 346

516 Summary 346References 346

52 Synthetic Molecules as Guides for DNA Nanostructure Formation 353521 Introduction 353522 Covalent insertion of synthetic molecules into DNA 353

5221 Incorporating organic molecules into DNA 3545222 Adjusting flexibility 354

52221 Mediating DNA self‐assembly 3555223 Direct effect of synthetic organic linkers on DNA stability and assembly 357

52231 Supramolecular assembly guided through synthetic additions to DNA 35952232 Backbone insertion of metal binding organic molecules 359

523 Non‐covalently guided DNA assembly 3645231 DNA intercalators 3645232 Groove binding 367

524 Conclusions 369References 369

53 DNA‐Based Nanostructuring with Branched Oligonucleotide Hybrids 375531 Introduction 375532 Branched oligonucleotides 377533 Hybrids with rigid cores 378534 Second‐generation hybrids with a rigid core 382535 Solution‐phase syntheses Synthetic challenges 385536 Hybrid materials 389537 Outlook 392538 Conclusions 394Acknowledgements 394References 394

54 DNA‐Controlled Assembly of Soft Nanoparticles 397541 Introduction 397542 Sequence design 399

5421 Double membrane anchor ssDNA design 3995422 Single membrane anchor multiple ssDNA design 3995423 Single membrane anchor multiple ssDNA design for irreversible

assembly (fusionhemifusion) 400

xii Contents

543 Lipid membrane anchors 400544 DNA‐controlled assembly studied by UV spectroscopy 402

5441 Thermal stability of lipid‐modified DNA conjugates 4045442 DNA mismatch discrimination studies 405

545 Assembly on solid support 406546 Assembly of giant unilamellar liposomes (GUVs) 408547 Conclusions 409Acknowledgements 409References 409

55 Metal Ions in Ribozymes and Riboswitches 412551 Introduction 412552 Coordination chemistry of RNA 413553 Ribozymes 415

5531 Overview of the ribozyme world 4155532 Small ribozymes 4155533 Large ribozymes 417

554 Riboswitches 4205541 Overview of the riboswitch world 4205542 Metal ions assisting riboswitch folding and ligand recognition 4225543 Riboswitch ligands containing a metal 423

55431 Mg2+‐sensing riboswitches 42355432 B

12‐riboswitches 424

55433 MoCoTuCo‐riboswitches 425555 Summary 425Acknowledgement 426References 426

56 DNA Switches and Machines 434561 Introduction 434562 Ion‐stimulated and photonicelectrical‐triggered DNA switches 438

5621 Ion‐stimulated DNA switches 4385622 Photonic and electrical triggering of DNA switches 443

563 Switchable DNA machines 4475631 Two‐state switchable DNA machines 4485632 Multi‐state DNA machines 455

564 Applications of DNA switches and machines 459565 Conclusions and perspectives 466References 467

57 DNA‐Based Asymmetric Catalysis 474571 Introduction 474572 Concept of DNA‐based asymmetric catalysis 474573 Design approaches in DNA‐based asymmetric catalysis 475574 Covalent anchoring 476

Contents xiii

575 Supramolecular anchoring 4785751 First generation DNA‐based catalysts 4785752 Improvement of the catalytic system ndash second generation catalysts 4785753 Catalytic scope of DNA‐based catalysts 479

57531 Conjugated addition reactions 48057532 Miscellaneous reactions 483

5754 Mechanistic studies and role of DNA in catalysis 48457541 DielsndashAlder cycloaddition 48557542 FriedelndashCrafts reaction 48657543 Michael addition 48657544 Hydration of enones 48757545 Stereochemistry in DNA‐based catalytic asymmetric reactions 487

576 Conclusions and perspectives 488References 489

Index 491

Philippe BartheacuteleacutemyUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Jacqueline K BartonDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Nina BerovaDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

Glenn A BurleyDepartment of Pure and Applied ChemistryUniversity of StrathclydeGlasgow UK

Niklaas J BuurmaPhysical Organic Chemistry CentreSchool of ChemistryCardiff UniversityCardiff UK

Jungkweon ChoiThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Jean‐Louis DupreyGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Alessandro DrsquoUrsoDepartment of ScienceUniversity of CataniaCatania Sicily Italy

George A EllestadDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

A ErbeHelmholtz‐Zentrum Dresden‐RossendorfInstitute of Ion Beam Physics and Materials ResearchDivision Scaling PhenomenaDresden Germany

Maria Elena FragalagraveDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Ariel L FurstDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

List of Contributors

xvi List of Contributors

Sofia GalloDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alice GhidiniKarolinska InstituteDepartment of Biosciences and NutritionNovum Sweden

Arnaud GissotUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Andrea GreschnerDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Helmut GriesserInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Michael A GrodickDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Anika KernDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

Alfonso LatorreInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Chun‐Hua LuInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Tetsuro MajimaThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Andriy MokhirFriedrich‐Alexander‐University Erlangen‐NuumlrnbergDepartment of Chemistry and PharmacyGermany

David MonchaudICMUB (Institut de Chimie Moleculaire Universite de Bourgogne)CNRS UMR6302Dijon France

Jens MuumlllerInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Merita MurtolaKarolinska InstituteDepartment of Biosciences and NutritionNovum Swedenand Department of ChemistryUniversity of TurkuTurku Finland

Anastasia MusiariDepartment of ChemistryUniversity of ZurichZurich Switzerland

List of Contributors xvii

Khalid OumzilUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Amit PatwaUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Ana G PetrovicDepartment of ChemistryColumbia UniversityHavemeyer Halland Department of Life SciencesNew York Institute of Technology (NYIT)New YorkNY USA

Fang PuLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Roberto PurrelloDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Hanna RadeckaDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jerzy RadeckiDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jinsong RenLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Clemens RichertInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Ana Rioz‐MartiacutenezStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Gerard RoelfesStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Fiora RosatiDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Magdalena Rowinska‐ZyrekDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alexander SchwengerInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Oliver SeitzDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

xviii List of Contributors

Mitsuhiko ShionoyaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Roland K O SigelDepartment of ChemistryUniversity of ZurichZurich Switzerland

Indranil SinhaInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Hanadi SleimanDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Aacutelvaro SomozaInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Peter StrazewskiInstitut de Chimie et Biochimie Moleacuteculaires et Supramoleacuteculaires (UMR 5246)Universiteacute de LyonLyon France

Roger StroumlmbergKarolinska InstituteDepartment of Biosciences and NutritionNovumSweden

Claudia StubinitzkyKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Yusuke TakezawaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Manuel A TamargoDepartment of ChemistryColumbia UniversityHavemeyer HallNew York NYUSA

Stefan VogelDepartment of PhysicsChemistry and PharmacyUniversity of Southern DenmarkBiomolecular Nanoscale Engineering Center (BioNEC)Denmark

Hans‐Achim WagenknechtKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Fuan WangInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Christian WellnerKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Itamar WillnerInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Kazushige YamanaDepartment of Materials Science and ChemistryUniversity of HyogoHimeji Japan

Notably one of the most influential scientific achievements of the last century concerns the structural elucidation of DNA by Watson Crick Franklin and Wilkins in 1953 [1] As was foreseen in their seminal papers the structure of DNA had profound implications on molecular biology

ldquoWe wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA) This structure has novel features which are of considerable biological interestrdquo

Since then the role of DNA in biology has been accepted as that of the bearer of the genetic code and many genomic sequences have been deciphered including the human genome However the story is far from over and many questions still remain to be answered in particular the details of how DNA works to fulfil its duties including the sequence dependent local structure protein binding to DNA regulation of gene expression (including methylation and selective unwinding from histones) to name but a few Also although knowledge of the three‐letter genetic code allows for the identification of genes and comparison between species to find similarities and heritage it also raises the question of the exact role of the non‐ coding regions of the genomes

Not long after the huge biological importance of DNA had been understood the fascinating features of this self‐assembled biopolymer began to inspire synthetic chemists analytical specialists biophysicists and even computer programmers to devote their research efforts to oligonucleotide‐based systems

The basic principle of the workings of DNA is simple the molecule forms a well‐understood double helix through the complementary base pairing of two antiparallel strands Yet there is far more to DNA than just this concept DNA can act both as a rigid stick (duplex) with a persistence length of about 40ndash50 nm and as a flexible glue (single strand) giving rise to a Lego‐like building block system for the creation of architectures with nanometre precision In addition more complex tertiary structures such as loops triple strands quadru-plexes and various junctions many of which have been found in vivo add to the countless possibilities of creating DNA structures with functions beyond those of just information storage and heredity The plethora of non‐duplex tertiary structures is even more pronounced in the RNA context

By taking DNA out of its biological environment new systems have emerged that are beginning to play a major role in materials science electronics diagnostics medicinal chemistry and much more The supramo-lecular aspects of DNA have seen significant advances in the past few decades particularly with the inclusion of modified nucleotides

Organic synthesis has and will remain a key aspect of DNA chemistry The concept of phosphoramidite chemistry for automated solid‐phase synthesis (SPS) of DNA as first described by Caruthers in 1981 [2] has on the whole remained unaltered as it has proven to be a most versatile approach In principle any diol can

Preface

xx Preface

be used for the stepwise build‐up of functional molecules as the concept is not restricted to nucleosides provided the other functional groups that are present are compatible with the strongly acidic basic and oxidising environment in SPS although milder conditions are also available In addition nucleosides can be chemically functionalised with almost any additional group be it small organic molecules or large metal complexes The combination of all accessible building blocks has lead to a system that is now being explored in almost all areas of science as mentioned earlier

The chapters in this book present an excellent collection of state‐of‐the‐art reviews covering research that is currently being carried out The chapters are devoted to the most important fields being studied

1 (Non‐) covalently modified DNA with novel functions2 DNA wires and electron transport through DNA3 Oligonucleotides in sensing and diagnostic applications4 Conjugation of DNA with biomolecules and nanoparticles5 Alternative DNA structures switches and nanomachines

Each chapter is devoted to a specialised topic within the larger context of DNA chemistry and will give the reader both an introduction to the field and the relevant technologies and a more focussed description of the authorsrsquo own research and viewpoint General conclusions and outlooks for the future are also given We are in the very lucky position of having been able to attract many of the key players in the relevant areas to devote their time to writing what we believe is an outstanding collection of well written and up‐to‐date chapters As the field is growing so rapidly it would be beyond the scope of any textbook to include everyone currently working in this field or to mention the excellent new ideas of every research group This demonstrates that applied DNA technology has reached the level at which it is playing a key role across the board

Nucleotide technology is a fast moving area where research is advancing rapidly However these chapters will certainly remain a key collection for some years to come Even though the systems will steadily improve the basic technologies presented and discussed here will remain the same for the foreseeable future as can be seen from the basic SPS principles The book is intended to give the novice an introduction and a basic overview of all aspects of nucleotide technology including strategies concepts and visions The experienced reader will have an up‐to‐date volume at hand where ndash through the amalgamation of very different ideas ndash novel applications and concepts may be conceived We are therefore convinced that this collection will be very useful to scientists at all levels and we hope that it will indeed trigger the emergence of new research

It is generally difficult if not impossible to predict where the future will take us as new results are being published on a daily basis sometimes in unrelated fields where the impact on onersquos own research may not be immediately evident Many of the approaches used today could not have been predicted ten years ago as some of the key technologies were not available then (eg DNA origami) DNA technology will continue to be important at both the giving and receiving ends DNA bio-nanotechnology will influence material medicinal and biological sciences whereas inventions and demands from those fields will have an impact on the direction of the development of DNA technology

We give great thanks to all contributors to this book and hope that the reader will enjoy it as much as we did during the editorial stages

Eugen StulzGuido H Clever

Preface xxi

References

[1] (a) R E Franklin and R G Gosling Molecular configuration in sodium thymonucleate Nature 1953 171 (4356) 740ndash741 (b) J D Watson and F H C Crick Molecular structure of nucleic acids A structure for deoxyribose nucleic acid Nature 1953 171 (4356) 737ndash738 (c) M H Wilkins A R Stokes and H R Wilson Molecular structure of nucleic acids Molecular structure of deoxypentose nucleic acids Nature 1953 171 (4356) 738ndash740

[2] (a) S L Beaucage and M H Caruthers Deoxynucleoside phosphoramidites ndash A new class of key intermediates for deoxypolynucleotide synthesis Tetrahedron Lett 1981 22 (20) 1859ndash1862 (b) M D Matteucci and M H and Caruthers Nucleotide Chemistry 4 Synthesis of deoxyoligonucleotides on a polymer support J Am Chem Soc 1981 103 (11) 3185ndash3191

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

xii Contents

543 Lipid membrane anchors 400544 DNA‐controlled assembly studied by UV spectroscopy 402

5441 Thermal stability of lipid‐modified DNA conjugates 4045442 DNA mismatch discrimination studies 405

545 Assembly on solid support 406546 Assembly of giant unilamellar liposomes (GUVs) 408547 Conclusions 409Acknowledgements 409References 409

55 Metal Ions in Ribozymes and Riboswitches 412551 Introduction 412552 Coordination chemistry of RNA 413553 Ribozymes 415

5531 Overview of the ribozyme world 4155532 Small ribozymes 4155533 Large ribozymes 417

554 Riboswitches 4205541 Overview of the riboswitch world 4205542 Metal ions assisting riboswitch folding and ligand recognition 4225543 Riboswitch ligands containing a metal 423

55431 Mg2+‐sensing riboswitches 42355432 B

12‐riboswitches 424

55433 MoCoTuCo‐riboswitches 425555 Summary 425Acknowledgement 426References 426

56 DNA Switches and Machines 434561 Introduction 434562 Ion‐stimulated and photonicelectrical‐triggered DNA switches 438

5621 Ion‐stimulated DNA switches 4385622 Photonic and electrical triggering of DNA switches 443

563 Switchable DNA machines 4475631 Two‐state switchable DNA machines 4485632 Multi‐state DNA machines 455

564 Applications of DNA switches and machines 459565 Conclusions and perspectives 466References 467

57 DNA‐Based Asymmetric Catalysis 474571 Introduction 474572 Concept of DNA‐based asymmetric catalysis 474573 Design approaches in DNA‐based asymmetric catalysis 475574 Covalent anchoring 476

Contents xiii

575 Supramolecular anchoring 4785751 First generation DNA‐based catalysts 4785752 Improvement of the catalytic system ndash second generation catalysts 4785753 Catalytic scope of DNA‐based catalysts 479

57531 Conjugated addition reactions 48057532 Miscellaneous reactions 483

5754 Mechanistic studies and role of DNA in catalysis 48457541 DielsndashAlder cycloaddition 48557542 FriedelndashCrafts reaction 48657543 Michael addition 48657544 Hydration of enones 48757545 Stereochemistry in DNA‐based catalytic asymmetric reactions 487

576 Conclusions and perspectives 488References 489

Index 491

Philippe BartheacuteleacutemyUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Jacqueline K BartonDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Nina BerovaDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

Glenn A BurleyDepartment of Pure and Applied ChemistryUniversity of StrathclydeGlasgow UK

Niklaas J BuurmaPhysical Organic Chemistry CentreSchool of ChemistryCardiff UniversityCardiff UK

Jungkweon ChoiThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Jean‐Louis DupreyGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Alessandro DrsquoUrsoDepartment of ScienceUniversity of CataniaCatania Sicily Italy

George A EllestadDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

A ErbeHelmholtz‐Zentrum Dresden‐RossendorfInstitute of Ion Beam Physics and Materials ResearchDivision Scaling PhenomenaDresden Germany

Maria Elena FragalagraveDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Ariel L FurstDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

List of Contributors

xvi List of Contributors

Sofia GalloDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alice GhidiniKarolinska InstituteDepartment of Biosciences and NutritionNovum Sweden

Arnaud GissotUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Andrea GreschnerDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Helmut GriesserInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Michael A GrodickDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Anika KernDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

Alfonso LatorreInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Chun‐Hua LuInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Tetsuro MajimaThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Andriy MokhirFriedrich‐Alexander‐University Erlangen‐NuumlrnbergDepartment of Chemistry and PharmacyGermany

David MonchaudICMUB (Institut de Chimie Moleculaire Universite de Bourgogne)CNRS UMR6302Dijon France

Jens MuumlllerInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Merita MurtolaKarolinska InstituteDepartment of Biosciences and NutritionNovum Swedenand Department of ChemistryUniversity of TurkuTurku Finland

Anastasia MusiariDepartment of ChemistryUniversity of ZurichZurich Switzerland

List of Contributors xvii

Khalid OumzilUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Amit PatwaUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Ana G PetrovicDepartment of ChemistryColumbia UniversityHavemeyer Halland Department of Life SciencesNew York Institute of Technology (NYIT)New YorkNY USA

Fang PuLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Roberto PurrelloDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Hanna RadeckaDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jerzy RadeckiDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jinsong RenLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Clemens RichertInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Ana Rioz‐MartiacutenezStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Gerard RoelfesStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Fiora RosatiDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Magdalena Rowinska‐ZyrekDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alexander SchwengerInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Oliver SeitzDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

xviii List of Contributors

Mitsuhiko ShionoyaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Roland K O SigelDepartment of ChemistryUniversity of ZurichZurich Switzerland

Indranil SinhaInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Hanadi SleimanDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Aacutelvaro SomozaInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Peter StrazewskiInstitut de Chimie et Biochimie Moleacuteculaires et Supramoleacuteculaires (UMR 5246)Universiteacute de LyonLyon France

Roger StroumlmbergKarolinska InstituteDepartment of Biosciences and NutritionNovumSweden

Claudia StubinitzkyKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Yusuke TakezawaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Manuel A TamargoDepartment of ChemistryColumbia UniversityHavemeyer HallNew York NYUSA

Stefan VogelDepartment of PhysicsChemistry and PharmacyUniversity of Southern DenmarkBiomolecular Nanoscale Engineering Center (BioNEC)Denmark

Hans‐Achim WagenknechtKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Fuan WangInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Christian WellnerKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Itamar WillnerInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Kazushige YamanaDepartment of Materials Science and ChemistryUniversity of HyogoHimeji Japan

Notably one of the most influential scientific achievements of the last century concerns the structural elucidation of DNA by Watson Crick Franklin and Wilkins in 1953 [1] As was foreseen in their seminal papers the structure of DNA had profound implications on molecular biology

ldquoWe wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA) This structure has novel features which are of considerable biological interestrdquo

Since then the role of DNA in biology has been accepted as that of the bearer of the genetic code and many genomic sequences have been deciphered including the human genome However the story is far from over and many questions still remain to be answered in particular the details of how DNA works to fulfil its duties including the sequence dependent local structure protein binding to DNA regulation of gene expression (including methylation and selective unwinding from histones) to name but a few Also although knowledge of the three‐letter genetic code allows for the identification of genes and comparison between species to find similarities and heritage it also raises the question of the exact role of the non‐ coding regions of the genomes

Not long after the huge biological importance of DNA had been understood the fascinating features of this self‐assembled biopolymer began to inspire synthetic chemists analytical specialists biophysicists and even computer programmers to devote their research efforts to oligonucleotide‐based systems

The basic principle of the workings of DNA is simple the molecule forms a well‐understood double helix through the complementary base pairing of two antiparallel strands Yet there is far more to DNA than just this concept DNA can act both as a rigid stick (duplex) with a persistence length of about 40ndash50 nm and as a flexible glue (single strand) giving rise to a Lego‐like building block system for the creation of architectures with nanometre precision In addition more complex tertiary structures such as loops triple strands quadru-plexes and various junctions many of which have been found in vivo add to the countless possibilities of creating DNA structures with functions beyond those of just information storage and heredity The plethora of non‐duplex tertiary structures is even more pronounced in the RNA context

By taking DNA out of its biological environment new systems have emerged that are beginning to play a major role in materials science electronics diagnostics medicinal chemistry and much more The supramo-lecular aspects of DNA have seen significant advances in the past few decades particularly with the inclusion of modified nucleotides

Organic synthesis has and will remain a key aspect of DNA chemistry The concept of phosphoramidite chemistry for automated solid‐phase synthesis (SPS) of DNA as first described by Caruthers in 1981 [2] has on the whole remained unaltered as it has proven to be a most versatile approach In principle any diol can

Preface

xx Preface

be used for the stepwise build‐up of functional molecules as the concept is not restricted to nucleosides provided the other functional groups that are present are compatible with the strongly acidic basic and oxidising environment in SPS although milder conditions are also available In addition nucleosides can be chemically functionalised with almost any additional group be it small organic molecules or large metal complexes The combination of all accessible building blocks has lead to a system that is now being explored in almost all areas of science as mentioned earlier

The chapters in this book present an excellent collection of state‐of‐the‐art reviews covering research that is currently being carried out The chapters are devoted to the most important fields being studied

1 (Non‐) covalently modified DNA with novel functions2 DNA wires and electron transport through DNA3 Oligonucleotides in sensing and diagnostic applications4 Conjugation of DNA with biomolecules and nanoparticles5 Alternative DNA structures switches and nanomachines

Each chapter is devoted to a specialised topic within the larger context of DNA chemistry and will give the reader both an introduction to the field and the relevant technologies and a more focussed description of the authorsrsquo own research and viewpoint General conclusions and outlooks for the future are also given We are in the very lucky position of having been able to attract many of the key players in the relevant areas to devote their time to writing what we believe is an outstanding collection of well written and up‐to‐date chapters As the field is growing so rapidly it would be beyond the scope of any textbook to include everyone currently working in this field or to mention the excellent new ideas of every research group This demonstrates that applied DNA technology has reached the level at which it is playing a key role across the board

Nucleotide technology is a fast moving area where research is advancing rapidly However these chapters will certainly remain a key collection for some years to come Even though the systems will steadily improve the basic technologies presented and discussed here will remain the same for the foreseeable future as can be seen from the basic SPS principles The book is intended to give the novice an introduction and a basic overview of all aspects of nucleotide technology including strategies concepts and visions The experienced reader will have an up‐to‐date volume at hand where ndash through the amalgamation of very different ideas ndash novel applications and concepts may be conceived We are therefore convinced that this collection will be very useful to scientists at all levels and we hope that it will indeed trigger the emergence of new research

It is generally difficult if not impossible to predict where the future will take us as new results are being published on a daily basis sometimes in unrelated fields where the impact on onersquos own research may not be immediately evident Many of the approaches used today could not have been predicted ten years ago as some of the key technologies were not available then (eg DNA origami) DNA technology will continue to be important at both the giving and receiving ends DNA bio-nanotechnology will influence material medicinal and biological sciences whereas inventions and demands from those fields will have an impact on the direction of the development of DNA technology

We give great thanks to all contributors to this book and hope that the reader will enjoy it as much as we did during the editorial stages

Eugen StulzGuido H Clever

Preface xxi

References

[1] (a) R E Franklin and R G Gosling Molecular configuration in sodium thymonucleate Nature 1953 171 (4356) 740ndash741 (b) J D Watson and F H C Crick Molecular structure of nucleic acids A structure for deoxyribose nucleic acid Nature 1953 171 (4356) 737ndash738 (c) M H Wilkins A R Stokes and H R Wilson Molecular structure of nucleic acids Molecular structure of deoxypentose nucleic acids Nature 1953 171 (4356) 738ndash740

[2] (a) S L Beaucage and M H Caruthers Deoxynucleoside phosphoramidites ndash A new class of key intermediates for deoxypolynucleotide synthesis Tetrahedron Lett 1981 22 (20) 1859ndash1862 (b) M D Matteucci and M H and Caruthers Nucleotide Chemistry 4 Synthesis of deoxyoligonucleotides on a polymer support J Am Chem Soc 1981 103 (11) 3185ndash3191

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

Contents xiii

575 Supramolecular anchoring 4785751 First generation DNA‐based catalysts 4785752 Improvement of the catalytic system ndash second generation catalysts 4785753 Catalytic scope of DNA‐based catalysts 479

57531 Conjugated addition reactions 48057532 Miscellaneous reactions 483

5754 Mechanistic studies and role of DNA in catalysis 48457541 DielsndashAlder cycloaddition 48557542 FriedelndashCrafts reaction 48657543 Michael addition 48657544 Hydration of enones 48757545 Stereochemistry in DNA‐based catalytic asymmetric reactions 487

576 Conclusions and perspectives 488References 489

Index 491

Philippe BartheacuteleacutemyUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Jacqueline K BartonDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Nina BerovaDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

Glenn A BurleyDepartment of Pure and Applied ChemistryUniversity of StrathclydeGlasgow UK

Niklaas J BuurmaPhysical Organic Chemistry CentreSchool of ChemistryCardiff UniversityCardiff UK

Jungkweon ChoiThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Jean‐Louis DupreyGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Alessandro DrsquoUrsoDepartment of ScienceUniversity of CataniaCatania Sicily Italy

George A EllestadDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

A ErbeHelmholtz‐Zentrum Dresden‐RossendorfInstitute of Ion Beam Physics and Materials ResearchDivision Scaling PhenomenaDresden Germany

Maria Elena FragalagraveDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Ariel L FurstDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

List of Contributors

xvi List of Contributors

Sofia GalloDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alice GhidiniKarolinska InstituteDepartment of Biosciences and NutritionNovum Sweden

Arnaud GissotUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Andrea GreschnerDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Helmut GriesserInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Michael A GrodickDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Anika KernDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

Alfonso LatorreInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Chun‐Hua LuInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Tetsuro MajimaThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Andriy MokhirFriedrich‐Alexander‐University Erlangen‐NuumlrnbergDepartment of Chemistry and PharmacyGermany

David MonchaudICMUB (Institut de Chimie Moleculaire Universite de Bourgogne)CNRS UMR6302Dijon France

Jens MuumlllerInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Merita MurtolaKarolinska InstituteDepartment of Biosciences and NutritionNovum Swedenand Department of ChemistryUniversity of TurkuTurku Finland

Anastasia MusiariDepartment of ChemistryUniversity of ZurichZurich Switzerland

List of Contributors xvii

Khalid OumzilUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Amit PatwaUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Ana G PetrovicDepartment of ChemistryColumbia UniversityHavemeyer Halland Department of Life SciencesNew York Institute of Technology (NYIT)New YorkNY USA

Fang PuLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Roberto PurrelloDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Hanna RadeckaDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jerzy RadeckiDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jinsong RenLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Clemens RichertInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Ana Rioz‐MartiacutenezStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Gerard RoelfesStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Fiora RosatiDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Magdalena Rowinska‐ZyrekDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alexander SchwengerInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Oliver SeitzDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

xviii List of Contributors

Mitsuhiko ShionoyaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Roland K O SigelDepartment of ChemistryUniversity of ZurichZurich Switzerland

Indranil SinhaInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Hanadi SleimanDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Aacutelvaro SomozaInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Peter StrazewskiInstitut de Chimie et Biochimie Moleacuteculaires et Supramoleacuteculaires (UMR 5246)Universiteacute de LyonLyon France

Roger StroumlmbergKarolinska InstituteDepartment of Biosciences and NutritionNovumSweden

Claudia StubinitzkyKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Yusuke TakezawaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Manuel A TamargoDepartment of ChemistryColumbia UniversityHavemeyer HallNew York NYUSA

Stefan VogelDepartment of PhysicsChemistry and PharmacyUniversity of Southern DenmarkBiomolecular Nanoscale Engineering Center (BioNEC)Denmark

Hans‐Achim WagenknechtKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Fuan WangInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Christian WellnerKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Itamar WillnerInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Kazushige YamanaDepartment of Materials Science and ChemistryUniversity of HyogoHimeji Japan

Notably one of the most influential scientific achievements of the last century concerns the structural elucidation of DNA by Watson Crick Franklin and Wilkins in 1953 [1] As was foreseen in their seminal papers the structure of DNA had profound implications on molecular biology

ldquoWe wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA) This structure has novel features which are of considerable biological interestrdquo

Since then the role of DNA in biology has been accepted as that of the bearer of the genetic code and many genomic sequences have been deciphered including the human genome However the story is far from over and many questions still remain to be answered in particular the details of how DNA works to fulfil its duties including the sequence dependent local structure protein binding to DNA regulation of gene expression (including methylation and selective unwinding from histones) to name but a few Also although knowledge of the three‐letter genetic code allows for the identification of genes and comparison between species to find similarities and heritage it also raises the question of the exact role of the non‐ coding regions of the genomes

Not long after the huge biological importance of DNA had been understood the fascinating features of this self‐assembled biopolymer began to inspire synthetic chemists analytical specialists biophysicists and even computer programmers to devote their research efforts to oligonucleotide‐based systems

The basic principle of the workings of DNA is simple the molecule forms a well‐understood double helix through the complementary base pairing of two antiparallel strands Yet there is far more to DNA than just this concept DNA can act both as a rigid stick (duplex) with a persistence length of about 40ndash50 nm and as a flexible glue (single strand) giving rise to a Lego‐like building block system for the creation of architectures with nanometre precision In addition more complex tertiary structures such as loops triple strands quadru-plexes and various junctions many of which have been found in vivo add to the countless possibilities of creating DNA structures with functions beyond those of just information storage and heredity The plethora of non‐duplex tertiary structures is even more pronounced in the RNA context

By taking DNA out of its biological environment new systems have emerged that are beginning to play a major role in materials science electronics diagnostics medicinal chemistry and much more The supramo-lecular aspects of DNA have seen significant advances in the past few decades particularly with the inclusion of modified nucleotides

Organic synthesis has and will remain a key aspect of DNA chemistry The concept of phosphoramidite chemistry for automated solid‐phase synthesis (SPS) of DNA as first described by Caruthers in 1981 [2] has on the whole remained unaltered as it has proven to be a most versatile approach In principle any diol can

Preface

xx Preface

be used for the stepwise build‐up of functional molecules as the concept is not restricted to nucleosides provided the other functional groups that are present are compatible with the strongly acidic basic and oxidising environment in SPS although milder conditions are also available In addition nucleosides can be chemically functionalised with almost any additional group be it small organic molecules or large metal complexes The combination of all accessible building blocks has lead to a system that is now being explored in almost all areas of science as mentioned earlier

The chapters in this book present an excellent collection of state‐of‐the‐art reviews covering research that is currently being carried out The chapters are devoted to the most important fields being studied

1 (Non‐) covalently modified DNA with novel functions2 DNA wires and electron transport through DNA3 Oligonucleotides in sensing and diagnostic applications4 Conjugation of DNA with biomolecules and nanoparticles5 Alternative DNA structures switches and nanomachines

Each chapter is devoted to a specialised topic within the larger context of DNA chemistry and will give the reader both an introduction to the field and the relevant technologies and a more focussed description of the authorsrsquo own research and viewpoint General conclusions and outlooks for the future are also given We are in the very lucky position of having been able to attract many of the key players in the relevant areas to devote their time to writing what we believe is an outstanding collection of well written and up‐to‐date chapters As the field is growing so rapidly it would be beyond the scope of any textbook to include everyone currently working in this field or to mention the excellent new ideas of every research group This demonstrates that applied DNA technology has reached the level at which it is playing a key role across the board

Nucleotide technology is a fast moving area where research is advancing rapidly However these chapters will certainly remain a key collection for some years to come Even though the systems will steadily improve the basic technologies presented and discussed here will remain the same for the foreseeable future as can be seen from the basic SPS principles The book is intended to give the novice an introduction and a basic overview of all aspects of nucleotide technology including strategies concepts and visions The experienced reader will have an up‐to‐date volume at hand where ndash through the amalgamation of very different ideas ndash novel applications and concepts may be conceived We are therefore convinced that this collection will be very useful to scientists at all levels and we hope that it will indeed trigger the emergence of new research

It is generally difficult if not impossible to predict where the future will take us as new results are being published on a daily basis sometimes in unrelated fields where the impact on onersquos own research may not be immediately evident Many of the approaches used today could not have been predicted ten years ago as some of the key technologies were not available then (eg DNA origami) DNA technology will continue to be important at both the giving and receiving ends DNA bio-nanotechnology will influence material medicinal and biological sciences whereas inventions and demands from those fields will have an impact on the direction of the development of DNA technology

We give great thanks to all contributors to this book and hope that the reader will enjoy it as much as we did during the editorial stages

Eugen StulzGuido H Clever

Preface xxi

References

[1] (a) R E Franklin and R G Gosling Molecular configuration in sodium thymonucleate Nature 1953 171 (4356) 740ndash741 (b) J D Watson and F H C Crick Molecular structure of nucleic acids A structure for deoxyribose nucleic acid Nature 1953 171 (4356) 737ndash738 (c) M H Wilkins A R Stokes and H R Wilson Molecular structure of nucleic acids Molecular structure of deoxypentose nucleic acids Nature 1953 171 (4356) 738ndash740

[2] (a) S L Beaucage and M H Caruthers Deoxynucleoside phosphoramidites ndash A new class of key intermediates for deoxypolynucleotide synthesis Tetrahedron Lett 1981 22 (20) 1859ndash1862 (b) M D Matteucci and M H and Caruthers Nucleotide Chemistry 4 Synthesis of deoxyoligonucleotides on a polymer support J Am Chem Soc 1981 103 (11) 3185ndash3191

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

Philippe BartheacuteleacutemyUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Jacqueline K BartonDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Nina BerovaDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

Glenn A BurleyDepartment of Pure and Applied ChemistryUniversity of StrathclydeGlasgow UK

Niklaas J BuurmaPhysical Organic Chemistry CentreSchool of ChemistryCardiff UniversityCardiff UK

Jungkweon ChoiThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Jean‐Louis DupreyGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Alessandro DrsquoUrsoDepartment of ScienceUniversity of CataniaCatania Sicily Italy

George A EllestadDepartment of ChemistryColumbia UniversityHavemeyer HallNew YorkNY USA

A ErbeHelmholtz‐Zentrum Dresden‐RossendorfInstitute of Ion Beam Physics and Materials ResearchDivision Scaling PhenomenaDresden Germany

Maria Elena FragalagraveDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Ariel L FurstDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

List of Contributors

xvi List of Contributors

Sofia GalloDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alice GhidiniKarolinska InstituteDepartment of Biosciences and NutritionNovum Sweden

Arnaud GissotUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Andrea GreschnerDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Helmut GriesserInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Michael A GrodickDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Anika KernDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

Alfonso LatorreInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Chun‐Hua LuInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Tetsuro MajimaThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Andriy MokhirFriedrich‐Alexander‐University Erlangen‐NuumlrnbergDepartment of Chemistry and PharmacyGermany

David MonchaudICMUB (Institut de Chimie Moleculaire Universite de Bourgogne)CNRS UMR6302Dijon France

Jens MuumlllerInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Merita MurtolaKarolinska InstituteDepartment of Biosciences and NutritionNovum Swedenand Department of ChemistryUniversity of TurkuTurku Finland

Anastasia MusiariDepartment of ChemistryUniversity of ZurichZurich Switzerland

List of Contributors xvii

Khalid OumzilUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Amit PatwaUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Ana G PetrovicDepartment of ChemistryColumbia UniversityHavemeyer Halland Department of Life SciencesNew York Institute of Technology (NYIT)New YorkNY USA

Fang PuLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Roberto PurrelloDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Hanna RadeckaDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jerzy RadeckiDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jinsong RenLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Clemens RichertInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Ana Rioz‐MartiacutenezStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Gerard RoelfesStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Fiora RosatiDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Magdalena Rowinska‐ZyrekDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alexander SchwengerInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Oliver SeitzDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

xviii List of Contributors

Mitsuhiko ShionoyaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Roland K O SigelDepartment of ChemistryUniversity of ZurichZurich Switzerland

Indranil SinhaInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Hanadi SleimanDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Aacutelvaro SomozaInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Peter StrazewskiInstitut de Chimie et Biochimie Moleacuteculaires et Supramoleacuteculaires (UMR 5246)Universiteacute de LyonLyon France

Roger StroumlmbergKarolinska InstituteDepartment of Biosciences and NutritionNovumSweden

Claudia StubinitzkyKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Yusuke TakezawaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Manuel A TamargoDepartment of ChemistryColumbia UniversityHavemeyer HallNew York NYUSA

Stefan VogelDepartment of PhysicsChemistry and PharmacyUniversity of Southern DenmarkBiomolecular Nanoscale Engineering Center (BioNEC)Denmark

Hans‐Achim WagenknechtKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Fuan WangInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Christian WellnerKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Itamar WillnerInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Kazushige YamanaDepartment of Materials Science and ChemistryUniversity of HyogoHimeji Japan

Notably one of the most influential scientific achievements of the last century concerns the structural elucidation of DNA by Watson Crick Franklin and Wilkins in 1953 [1] As was foreseen in their seminal papers the structure of DNA had profound implications on molecular biology

ldquoWe wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA) This structure has novel features which are of considerable biological interestrdquo

Since then the role of DNA in biology has been accepted as that of the bearer of the genetic code and many genomic sequences have been deciphered including the human genome However the story is far from over and many questions still remain to be answered in particular the details of how DNA works to fulfil its duties including the sequence dependent local structure protein binding to DNA regulation of gene expression (including methylation and selective unwinding from histones) to name but a few Also although knowledge of the three‐letter genetic code allows for the identification of genes and comparison between species to find similarities and heritage it also raises the question of the exact role of the non‐ coding regions of the genomes

Not long after the huge biological importance of DNA had been understood the fascinating features of this self‐assembled biopolymer began to inspire synthetic chemists analytical specialists biophysicists and even computer programmers to devote their research efforts to oligonucleotide‐based systems

The basic principle of the workings of DNA is simple the molecule forms a well‐understood double helix through the complementary base pairing of two antiparallel strands Yet there is far more to DNA than just this concept DNA can act both as a rigid stick (duplex) with a persistence length of about 40ndash50 nm and as a flexible glue (single strand) giving rise to a Lego‐like building block system for the creation of architectures with nanometre precision In addition more complex tertiary structures such as loops triple strands quadru-plexes and various junctions many of which have been found in vivo add to the countless possibilities of creating DNA structures with functions beyond those of just information storage and heredity The plethora of non‐duplex tertiary structures is even more pronounced in the RNA context

By taking DNA out of its biological environment new systems have emerged that are beginning to play a major role in materials science electronics diagnostics medicinal chemistry and much more The supramo-lecular aspects of DNA have seen significant advances in the past few decades particularly with the inclusion of modified nucleotides

Organic synthesis has and will remain a key aspect of DNA chemistry The concept of phosphoramidite chemistry for automated solid‐phase synthesis (SPS) of DNA as first described by Caruthers in 1981 [2] has on the whole remained unaltered as it has proven to be a most versatile approach In principle any diol can

Preface

xx Preface

be used for the stepwise build‐up of functional molecules as the concept is not restricted to nucleosides provided the other functional groups that are present are compatible with the strongly acidic basic and oxidising environment in SPS although milder conditions are also available In addition nucleosides can be chemically functionalised with almost any additional group be it small organic molecules or large metal complexes The combination of all accessible building blocks has lead to a system that is now being explored in almost all areas of science as mentioned earlier

The chapters in this book present an excellent collection of state‐of‐the‐art reviews covering research that is currently being carried out The chapters are devoted to the most important fields being studied

1 (Non‐) covalently modified DNA with novel functions2 DNA wires and electron transport through DNA3 Oligonucleotides in sensing and diagnostic applications4 Conjugation of DNA with biomolecules and nanoparticles5 Alternative DNA structures switches and nanomachines

Each chapter is devoted to a specialised topic within the larger context of DNA chemistry and will give the reader both an introduction to the field and the relevant technologies and a more focussed description of the authorsrsquo own research and viewpoint General conclusions and outlooks for the future are also given We are in the very lucky position of having been able to attract many of the key players in the relevant areas to devote their time to writing what we believe is an outstanding collection of well written and up‐to‐date chapters As the field is growing so rapidly it would be beyond the scope of any textbook to include everyone currently working in this field or to mention the excellent new ideas of every research group This demonstrates that applied DNA technology has reached the level at which it is playing a key role across the board

Nucleotide technology is a fast moving area where research is advancing rapidly However these chapters will certainly remain a key collection for some years to come Even though the systems will steadily improve the basic technologies presented and discussed here will remain the same for the foreseeable future as can be seen from the basic SPS principles The book is intended to give the novice an introduction and a basic overview of all aspects of nucleotide technology including strategies concepts and visions The experienced reader will have an up‐to‐date volume at hand where ndash through the amalgamation of very different ideas ndash novel applications and concepts may be conceived We are therefore convinced that this collection will be very useful to scientists at all levels and we hope that it will indeed trigger the emergence of new research

It is generally difficult if not impossible to predict where the future will take us as new results are being published on a daily basis sometimes in unrelated fields where the impact on onersquos own research may not be immediately evident Many of the approaches used today could not have been predicted ten years ago as some of the key technologies were not available then (eg DNA origami) DNA technology will continue to be important at both the giving and receiving ends DNA bio-nanotechnology will influence material medicinal and biological sciences whereas inventions and demands from those fields will have an impact on the direction of the development of DNA technology

We give great thanks to all contributors to this book and hope that the reader will enjoy it as much as we did during the editorial stages

Eugen StulzGuido H Clever

Preface xxi

References

[1] (a) R E Franklin and R G Gosling Molecular configuration in sodium thymonucleate Nature 1953 171 (4356) 740ndash741 (b) J D Watson and F H C Crick Molecular structure of nucleic acids A structure for deoxyribose nucleic acid Nature 1953 171 (4356) 737ndash738 (c) M H Wilkins A R Stokes and H R Wilson Molecular structure of nucleic acids Molecular structure of deoxypentose nucleic acids Nature 1953 171 (4356) 738ndash740

[2] (a) S L Beaucage and M H Caruthers Deoxynucleoside phosphoramidites ndash A new class of key intermediates for deoxypolynucleotide synthesis Tetrahedron Lett 1981 22 (20) 1859ndash1862 (b) M D Matteucci and M H and Caruthers Nucleotide Chemistry 4 Synthesis of deoxyoligonucleotides on a polymer support J Am Chem Soc 1981 103 (11) 3185ndash3191

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

xvi List of Contributors

Sofia GalloDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alice GhidiniKarolinska InstituteDepartment of Biosciences and NutritionNovum Sweden

Arnaud GissotUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Andrea GreschnerDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Helmut GriesserInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Michael A GrodickDivision of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadenaCA USA

Anika KernDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

Alfonso LatorreInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Chun‐Hua LuInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Tetsuro MajimaThe Institute of Scientific and Industrial Research (SANKEN)Osaka UniversityIbaraki Osaka Japan

Andriy MokhirFriedrich‐Alexander‐University Erlangen‐NuumlrnbergDepartment of Chemistry and PharmacyGermany

David MonchaudICMUB (Institut de Chimie Moleculaire Universite de Bourgogne)CNRS UMR6302Dijon France

Jens MuumlllerInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Merita MurtolaKarolinska InstituteDepartment of Biosciences and NutritionNovum Swedenand Department of ChemistryUniversity of TurkuTurku Finland

Anastasia MusiariDepartment of ChemistryUniversity of ZurichZurich Switzerland

List of Contributors xvii

Khalid OumzilUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Amit PatwaUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Ana G PetrovicDepartment of ChemistryColumbia UniversityHavemeyer Halland Department of Life SciencesNew York Institute of Technology (NYIT)New YorkNY USA

Fang PuLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Roberto PurrelloDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Hanna RadeckaDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jerzy RadeckiDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jinsong RenLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Clemens RichertInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Ana Rioz‐MartiacutenezStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Gerard RoelfesStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Fiora RosatiDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Magdalena Rowinska‐ZyrekDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alexander SchwengerInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Oliver SeitzDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

xviii List of Contributors

Mitsuhiko ShionoyaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Roland K O SigelDepartment of ChemistryUniversity of ZurichZurich Switzerland

Indranil SinhaInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Hanadi SleimanDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Aacutelvaro SomozaInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Peter StrazewskiInstitut de Chimie et Biochimie Moleacuteculaires et Supramoleacuteculaires (UMR 5246)Universiteacute de LyonLyon France

Roger StroumlmbergKarolinska InstituteDepartment of Biosciences and NutritionNovumSweden

Claudia StubinitzkyKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Yusuke TakezawaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Manuel A TamargoDepartment of ChemistryColumbia UniversityHavemeyer HallNew York NYUSA

Stefan VogelDepartment of PhysicsChemistry and PharmacyUniversity of Southern DenmarkBiomolecular Nanoscale Engineering Center (BioNEC)Denmark

Hans‐Achim WagenknechtKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Fuan WangInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Christian WellnerKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Itamar WillnerInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Kazushige YamanaDepartment of Materials Science and ChemistryUniversity of HyogoHimeji Japan

Notably one of the most influential scientific achievements of the last century concerns the structural elucidation of DNA by Watson Crick Franklin and Wilkins in 1953 [1] As was foreseen in their seminal papers the structure of DNA had profound implications on molecular biology

ldquoWe wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA) This structure has novel features which are of considerable biological interestrdquo

Since then the role of DNA in biology has been accepted as that of the bearer of the genetic code and many genomic sequences have been deciphered including the human genome However the story is far from over and many questions still remain to be answered in particular the details of how DNA works to fulfil its duties including the sequence dependent local structure protein binding to DNA regulation of gene expression (including methylation and selective unwinding from histones) to name but a few Also although knowledge of the three‐letter genetic code allows for the identification of genes and comparison between species to find similarities and heritage it also raises the question of the exact role of the non‐ coding regions of the genomes

Not long after the huge biological importance of DNA had been understood the fascinating features of this self‐assembled biopolymer began to inspire synthetic chemists analytical specialists biophysicists and even computer programmers to devote their research efforts to oligonucleotide‐based systems

The basic principle of the workings of DNA is simple the molecule forms a well‐understood double helix through the complementary base pairing of two antiparallel strands Yet there is far more to DNA than just this concept DNA can act both as a rigid stick (duplex) with a persistence length of about 40ndash50 nm and as a flexible glue (single strand) giving rise to a Lego‐like building block system for the creation of architectures with nanometre precision In addition more complex tertiary structures such as loops triple strands quadru-plexes and various junctions many of which have been found in vivo add to the countless possibilities of creating DNA structures with functions beyond those of just information storage and heredity The plethora of non‐duplex tertiary structures is even more pronounced in the RNA context

By taking DNA out of its biological environment new systems have emerged that are beginning to play a major role in materials science electronics diagnostics medicinal chemistry and much more The supramo-lecular aspects of DNA have seen significant advances in the past few decades particularly with the inclusion of modified nucleotides

Organic synthesis has and will remain a key aspect of DNA chemistry The concept of phosphoramidite chemistry for automated solid‐phase synthesis (SPS) of DNA as first described by Caruthers in 1981 [2] has on the whole remained unaltered as it has proven to be a most versatile approach In principle any diol can

Preface

xx Preface

be used for the stepwise build‐up of functional molecules as the concept is not restricted to nucleosides provided the other functional groups that are present are compatible with the strongly acidic basic and oxidising environment in SPS although milder conditions are also available In addition nucleosides can be chemically functionalised with almost any additional group be it small organic molecules or large metal complexes The combination of all accessible building blocks has lead to a system that is now being explored in almost all areas of science as mentioned earlier

The chapters in this book present an excellent collection of state‐of‐the‐art reviews covering research that is currently being carried out The chapters are devoted to the most important fields being studied

1 (Non‐) covalently modified DNA with novel functions2 DNA wires and electron transport through DNA3 Oligonucleotides in sensing and diagnostic applications4 Conjugation of DNA with biomolecules and nanoparticles5 Alternative DNA structures switches and nanomachines

Each chapter is devoted to a specialised topic within the larger context of DNA chemistry and will give the reader both an introduction to the field and the relevant technologies and a more focussed description of the authorsrsquo own research and viewpoint General conclusions and outlooks for the future are also given We are in the very lucky position of having been able to attract many of the key players in the relevant areas to devote their time to writing what we believe is an outstanding collection of well written and up‐to‐date chapters As the field is growing so rapidly it would be beyond the scope of any textbook to include everyone currently working in this field or to mention the excellent new ideas of every research group This demonstrates that applied DNA technology has reached the level at which it is playing a key role across the board

Nucleotide technology is a fast moving area where research is advancing rapidly However these chapters will certainly remain a key collection for some years to come Even though the systems will steadily improve the basic technologies presented and discussed here will remain the same for the foreseeable future as can be seen from the basic SPS principles The book is intended to give the novice an introduction and a basic overview of all aspects of nucleotide technology including strategies concepts and visions The experienced reader will have an up‐to‐date volume at hand where ndash through the amalgamation of very different ideas ndash novel applications and concepts may be conceived We are therefore convinced that this collection will be very useful to scientists at all levels and we hope that it will indeed trigger the emergence of new research

It is generally difficult if not impossible to predict where the future will take us as new results are being published on a daily basis sometimes in unrelated fields where the impact on onersquos own research may not be immediately evident Many of the approaches used today could not have been predicted ten years ago as some of the key technologies were not available then (eg DNA origami) DNA technology will continue to be important at both the giving and receiving ends DNA bio-nanotechnology will influence material medicinal and biological sciences whereas inventions and demands from those fields will have an impact on the direction of the development of DNA technology

We give great thanks to all contributors to this book and hope that the reader will enjoy it as much as we did during the editorial stages

Eugen StulzGuido H Clever

Preface xxi

References

[1] (a) R E Franklin and R G Gosling Molecular configuration in sodium thymonucleate Nature 1953 171 (4356) 740ndash741 (b) J D Watson and F H C Crick Molecular structure of nucleic acids A structure for deoxyribose nucleic acid Nature 1953 171 (4356) 737ndash738 (c) M H Wilkins A R Stokes and H R Wilson Molecular structure of nucleic acids Molecular structure of deoxypentose nucleic acids Nature 1953 171 (4356) 738ndash740

[2] (a) S L Beaucage and M H Caruthers Deoxynucleoside phosphoramidites ndash A new class of key intermediates for deoxypolynucleotide synthesis Tetrahedron Lett 1981 22 (20) 1859ndash1862 (b) M D Matteucci and M H and Caruthers Nucleotide Chemistry 4 Synthesis of deoxyoligonucleotides on a polymer support J Am Chem Soc 1981 103 (11) 3185ndash3191

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

List of Contributors xvii

Khalid OumzilUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Amit PatwaUniversiteacute Victor Segalen Bordeaux 2UFR Sciences de la Vieand INSERM U869Bordeaux France

Ana G PetrovicDepartment of ChemistryColumbia UniversityHavemeyer Halland Department of Life SciencesNew York Institute of Technology (NYIT)New YorkNY USA

Fang PuLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Roberto PurrelloDepartment of ScienceUniversity of CataniaCatania Sicily Italy

Hanna RadeckaDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jerzy RadeckiDepartment of BiosensorsInstitute of Animal Reproduction and Food Research of Polish Academy of SciencesOlsztyn Poland

Jinsong RenLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources UtilizationChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun China

Clemens RichertInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Ana Rioz‐MartiacutenezStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Gerard RoelfesStratingh Institute for ChemistryUniversity of GroningenGroningen The Netherlands

Fiora RosatiDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Magdalena Rowinska‐ZyrekDepartment of ChemistryUniversity of ZurichZurich Switzerland

Alexander SchwengerInstitute for Organic ChemistryUniversity of StuttgartStuttgart Germany

Oliver SeitzDepartment of Organic and Bioinorganic ChemistryHumboldt‐University of BerlinBerlin Germany

xviii List of Contributors

Mitsuhiko ShionoyaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Roland K O SigelDepartment of ChemistryUniversity of ZurichZurich Switzerland

Indranil SinhaInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Hanadi SleimanDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Aacutelvaro SomozaInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Peter StrazewskiInstitut de Chimie et Biochimie Moleacuteculaires et Supramoleacuteculaires (UMR 5246)Universiteacute de LyonLyon France

Roger StroumlmbergKarolinska InstituteDepartment of Biosciences and NutritionNovumSweden

Claudia StubinitzkyKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Yusuke TakezawaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Manuel A TamargoDepartment of ChemistryColumbia UniversityHavemeyer HallNew York NYUSA

Stefan VogelDepartment of PhysicsChemistry and PharmacyUniversity of Southern DenmarkBiomolecular Nanoscale Engineering Center (BioNEC)Denmark

Hans‐Achim WagenknechtKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Fuan WangInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Christian WellnerKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Itamar WillnerInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Kazushige YamanaDepartment of Materials Science and ChemistryUniversity of HyogoHimeji Japan

Notably one of the most influential scientific achievements of the last century concerns the structural elucidation of DNA by Watson Crick Franklin and Wilkins in 1953 [1] As was foreseen in their seminal papers the structure of DNA had profound implications on molecular biology

ldquoWe wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA) This structure has novel features which are of considerable biological interestrdquo

Since then the role of DNA in biology has been accepted as that of the bearer of the genetic code and many genomic sequences have been deciphered including the human genome However the story is far from over and many questions still remain to be answered in particular the details of how DNA works to fulfil its duties including the sequence dependent local structure protein binding to DNA regulation of gene expression (including methylation and selective unwinding from histones) to name but a few Also although knowledge of the three‐letter genetic code allows for the identification of genes and comparison between species to find similarities and heritage it also raises the question of the exact role of the non‐ coding regions of the genomes

Not long after the huge biological importance of DNA had been understood the fascinating features of this self‐assembled biopolymer began to inspire synthetic chemists analytical specialists biophysicists and even computer programmers to devote their research efforts to oligonucleotide‐based systems

The basic principle of the workings of DNA is simple the molecule forms a well‐understood double helix through the complementary base pairing of two antiparallel strands Yet there is far more to DNA than just this concept DNA can act both as a rigid stick (duplex) with a persistence length of about 40ndash50 nm and as a flexible glue (single strand) giving rise to a Lego‐like building block system for the creation of architectures with nanometre precision In addition more complex tertiary structures such as loops triple strands quadru-plexes and various junctions many of which have been found in vivo add to the countless possibilities of creating DNA structures with functions beyond those of just information storage and heredity The plethora of non‐duplex tertiary structures is even more pronounced in the RNA context

By taking DNA out of its biological environment new systems have emerged that are beginning to play a major role in materials science electronics diagnostics medicinal chemistry and much more The supramo-lecular aspects of DNA have seen significant advances in the past few decades particularly with the inclusion of modified nucleotides

Organic synthesis has and will remain a key aspect of DNA chemistry The concept of phosphoramidite chemistry for automated solid‐phase synthesis (SPS) of DNA as first described by Caruthers in 1981 [2] has on the whole remained unaltered as it has proven to be a most versatile approach In principle any diol can

Preface

xx Preface

be used for the stepwise build‐up of functional molecules as the concept is not restricted to nucleosides provided the other functional groups that are present are compatible with the strongly acidic basic and oxidising environment in SPS although milder conditions are also available In addition nucleosides can be chemically functionalised with almost any additional group be it small organic molecules or large metal complexes The combination of all accessible building blocks has lead to a system that is now being explored in almost all areas of science as mentioned earlier

The chapters in this book present an excellent collection of state‐of‐the‐art reviews covering research that is currently being carried out The chapters are devoted to the most important fields being studied

1 (Non‐) covalently modified DNA with novel functions2 DNA wires and electron transport through DNA3 Oligonucleotides in sensing and diagnostic applications4 Conjugation of DNA with biomolecules and nanoparticles5 Alternative DNA structures switches and nanomachines

Each chapter is devoted to a specialised topic within the larger context of DNA chemistry and will give the reader both an introduction to the field and the relevant technologies and a more focussed description of the authorsrsquo own research and viewpoint General conclusions and outlooks for the future are also given We are in the very lucky position of having been able to attract many of the key players in the relevant areas to devote their time to writing what we believe is an outstanding collection of well written and up‐to‐date chapters As the field is growing so rapidly it would be beyond the scope of any textbook to include everyone currently working in this field or to mention the excellent new ideas of every research group This demonstrates that applied DNA technology has reached the level at which it is playing a key role across the board

Nucleotide technology is a fast moving area where research is advancing rapidly However these chapters will certainly remain a key collection for some years to come Even though the systems will steadily improve the basic technologies presented and discussed here will remain the same for the foreseeable future as can be seen from the basic SPS principles The book is intended to give the novice an introduction and a basic overview of all aspects of nucleotide technology including strategies concepts and visions The experienced reader will have an up‐to‐date volume at hand where ndash through the amalgamation of very different ideas ndash novel applications and concepts may be conceived We are therefore convinced that this collection will be very useful to scientists at all levels and we hope that it will indeed trigger the emergence of new research

It is generally difficult if not impossible to predict where the future will take us as new results are being published on a daily basis sometimes in unrelated fields where the impact on onersquos own research may not be immediately evident Many of the approaches used today could not have been predicted ten years ago as some of the key technologies were not available then (eg DNA origami) DNA technology will continue to be important at both the giving and receiving ends DNA bio-nanotechnology will influence material medicinal and biological sciences whereas inventions and demands from those fields will have an impact on the direction of the development of DNA technology

We give great thanks to all contributors to this book and hope that the reader will enjoy it as much as we did during the editorial stages

Eugen StulzGuido H Clever

Preface xxi

References

[1] (a) R E Franklin and R G Gosling Molecular configuration in sodium thymonucleate Nature 1953 171 (4356) 740ndash741 (b) J D Watson and F H C Crick Molecular structure of nucleic acids A structure for deoxyribose nucleic acid Nature 1953 171 (4356) 737ndash738 (c) M H Wilkins A R Stokes and H R Wilson Molecular structure of nucleic acids Molecular structure of deoxypentose nucleic acids Nature 1953 171 (4356) 738ndash740

[2] (a) S L Beaucage and M H Caruthers Deoxynucleoside phosphoramidites ndash A new class of key intermediates for deoxypolynucleotide synthesis Tetrahedron Lett 1981 22 (20) 1859ndash1862 (b) M D Matteucci and M H and Caruthers Nucleotide Chemistry 4 Synthesis of deoxyoligonucleotides on a polymer support J Am Chem Soc 1981 103 (11) 3185ndash3191

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

xviii List of Contributors

Mitsuhiko ShionoyaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Roland K O SigelDepartment of ChemistryUniversity of ZurichZurich Switzerland

Indranil SinhaInstitute for Inorganic and Analytical ChemistryUniversity of MuumlnsterMuumlnster Germany

Hanadi SleimanDepartment of ChemistryMcGill UniversityMontreal Quebec Canada

Aacutelvaro SomozaInstituto Madrilentildeo de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) and CNB‐CSIC‐IMDEA Nanociencia Associated Unit ldquoUnidad de NanobiotecnologiacuteardquoMadrid Spain

Peter StrazewskiInstitut de Chimie et Biochimie Moleacuteculaires et Supramoleacuteculaires (UMR 5246)Universiteacute de LyonLyon France

Roger StroumlmbergKarolinska InstituteDepartment of Biosciences and NutritionNovumSweden

Claudia StubinitzkyKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Yusuke TakezawaGraduate School of ScienceDepartment of ChemistryThe University of TokyoTokyo Japan

Manuel A TamargoDepartment of ChemistryColumbia UniversityHavemeyer HallNew York NYUSA

Stefan VogelDepartment of PhysicsChemistry and PharmacyUniversity of Southern DenmarkBiomolecular Nanoscale Engineering Center (BioNEC)Denmark

Hans‐Achim WagenknechtKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Fuan WangInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Christian WellnerKarlsruhe Institute of Technology (KIT) Institute of Organic Chemistry-Chair II Karlsruhe Germany

Itamar WillnerInstitute of ChemistryThe Center for Nanoscience and NanotechnologyThe Hebrew University of JerusalemJerusalem Israel

Kazushige YamanaDepartment of Materials Science and ChemistryUniversity of HyogoHimeji Japan

Notably one of the most influential scientific achievements of the last century concerns the structural elucidation of DNA by Watson Crick Franklin and Wilkins in 1953 [1] As was foreseen in their seminal papers the structure of DNA had profound implications on molecular biology

ldquoWe wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA) This structure has novel features which are of considerable biological interestrdquo

Since then the role of DNA in biology has been accepted as that of the bearer of the genetic code and many genomic sequences have been deciphered including the human genome However the story is far from over and many questions still remain to be answered in particular the details of how DNA works to fulfil its duties including the sequence dependent local structure protein binding to DNA regulation of gene expression (including methylation and selective unwinding from histones) to name but a few Also although knowledge of the three‐letter genetic code allows for the identification of genes and comparison between species to find similarities and heritage it also raises the question of the exact role of the non‐ coding regions of the genomes

Not long after the huge biological importance of DNA had been understood the fascinating features of this self‐assembled biopolymer began to inspire synthetic chemists analytical specialists biophysicists and even computer programmers to devote their research efforts to oligonucleotide‐based systems

The basic principle of the workings of DNA is simple the molecule forms a well‐understood double helix through the complementary base pairing of two antiparallel strands Yet there is far more to DNA than just this concept DNA can act both as a rigid stick (duplex) with a persistence length of about 40ndash50 nm and as a flexible glue (single strand) giving rise to a Lego‐like building block system for the creation of architectures with nanometre precision In addition more complex tertiary structures such as loops triple strands quadru-plexes and various junctions many of which have been found in vivo add to the countless possibilities of creating DNA structures with functions beyond those of just information storage and heredity The plethora of non‐duplex tertiary structures is even more pronounced in the RNA context

By taking DNA out of its biological environment new systems have emerged that are beginning to play a major role in materials science electronics diagnostics medicinal chemistry and much more The supramo-lecular aspects of DNA have seen significant advances in the past few decades particularly with the inclusion of modified nucleotides

Organic synthesis has and will remain a key aspect of DNA chemistry The concept of phosphoramidite chemistry for automated solid‐phase synthesis (SPS) of DNA as first described by Caruthers in 1981 [2] has on the whole remained unaltered as it has proven to be a most versatile approach In principle any diol can

Preface

xx Preface

be used for the stepwise build‐up of functional molecules as the concept is not restricted to nucleosides provided the other functional groups that are present are compatible with the strongly acidic basic and oxidising environment in SPS although milder conditions are also available In addition nucleosides can be chemically functionalised with almost any additional group be it small organic molecules or large metal complexes The combination of all accessible building blocks has lead to a system that is now being explored in almost all areas of science as mentioned earlier

The chapters in this book present an excellent collection of state‐of‐the‐art reviews covering research that is currently being carried out The chapters are devoted to the most important fields being studied

1 (Non‐) covalently modified DNA with novel functions2 DNA wires and electron transport through DNA3 Oligonucleotides in sensing and diagnostic applications4 Conjugation of DNA with biomolecules and nanoparticles5 Alternative DNA structures switches and nanomachines

Each chapter is devoted to a specialised topic within the larger context of DNA chemistry and will give the reader both an introduction to the field and the relevant technologies and a more focussed description of the authorsrsquo own research and viewpoint General conclusions and outlooks for the future are also given We are in the very lucky position of having been able to attract many of the key players in the relevant areas to devote their time to writing what we believe is an outstanding collection of well written and up‐to‐date chapters As the field is growing so rapidly it would be beyond the scope of any textbook to include everyone currently working in this field or to mention the excellent new ideas of every research group This demonstrates that applied DNA technology has reached the level at which it is playing a key role across the board

Nucleotide technology is a fast moving area where research is advancing rapidly However these chapters will certainly remain a key collection for some years to come Even though the systems will steadily improve the basic technologies presented and discussed here will remain the same for the foreseeable future as can be seen from the basic SPS principles The book is intended to give the novice an introduction and a basic overview of all aspects of nucleotide technology including strategies concepts and visions The experienced reader will have an up‐to‐date volume at hand where ndash through the amalgamation of very different ideas ndash novel applications and concepts may be conceived We are therefore convinced that this collection will be very useful to scientists at all levels and we hope that it will indeed trigger the emergence of new research

It is generally difficult if not impossible to predict where the future will take us as new results are being published on a daily basis sometimes in unrelated fields where the impact on onersquos own research may not be immediately evident Many of the approaches used today could not have been predicted ten years ago as some of the key technologies were not available then (eg DNA origami) DNA technology will continue to be important at both the giving and receiving ends DNA bio-nanotechnology will influence material medicinal and biological sciences whereas inventions and demands from those fields will have an impact on the direction of the development of DNA technology

We give great thanks to all contributors to this book and hope that the reader will enjoy it as much as we did during the editorial stages

Eugen StulzGuido H Clever

Preface xxi

References

[1] (a) R E Franklin and R G Gosling Molecular configuration in sodium thymonucleate Nature 1953 171 (4356) 740ndash741 (b) J D Watson and F H C Crick Molecular structure of nucleic acids A structure for deoxyribose nucleic acid Nature 1953 171 (4356) 737ndash738 (c) M H Wilkins A R Stokes and H R Wilson Molecular structure of nucleic acids Molecular structure of deoxypentose nucleic acids Nature 1953 171 (4356) 738ndash740

[2] (a) S L Beaucage and M H Caruthers Deoxynucleoside phosphoramidites ndash A new class of key intermediates for deoxypolynucleotide synthesis Tetrahedron Lett 1981 22 (20) 1859ndash1862 (b) M D Matteucci and M H and Caruthers Nucleotide Chemistry 4 Synthesis of deoxyoligonucleotides on a polymer support J Am Chem Soc 1981 103 (11) 3185ndash3191

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

Notably one of the most influential scientific achievements of the last century concerns the structural elucidation of DNA by Watson Crick Franklin and Wilkins in 1953 [1] As was foreseen in their seminal papers the structure of DNA had profound implications on molecular biology

ldquoWe wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA) This structure has novel features which are of considerable biological interestrdquo

Since then the role of DNA in biology has been accepted as that of the bearer of the genetic code and many genomic sequences have been deciphered including the human genome However the story is far from over and many questions still remain to be answered in particular the details of how DNA works to fulfil its duties including the sequence dependent local structure protein binding to DNA regulation of gene expression (including methylation and selective unwinding from histones) to name but a few Also although knowledge of the three‐letter genetic code allows for the identification of genes and comparison between species to find similarities and heritage it also raises the question of the exact role of the non‐ coding regions of the genomes

Not long after the huge biological importance of DNA had been understood the fascinating features of this self‐assembled biopolymer began to inspire synthetic chemists analytical specialists biophysicists and even computer programmers to devote their research efforts to oligonucleotide‐based systems

The basic principle of the workings of DNA is simple the molecule forms a well‐understood double helix through the complementary base pairing of two antiparallel strands Yet there is far more to DNA than just this concept DNA can act both as a rigid stick (duplex) with a persistence length of about 40ndash50 nm and as a flexible glue (single strand) giving rise to a Lego‐like building block system for the creation of architectures with nanometre precision In addition more complex tertiary structures such as loops triple strands quadru-plexes and various junctions many of which have been found in vivo add to the countless possibilities of creating DNA structures with functions beyond those of just information storage and heredity The plethora of non‐duplex tertiary structures is even more pronounced in the RNA context

By taking DNA out of its biological environment new systems have emerged that are beginning to play a major role in materials science electronics diagnostics medicinal chemistry and much more The supramo-lecular aspects of DNA have seen significant advances in the past few decades particularly with the inclusion of modified nucleotides

Organic synthesis has and will remain a key aspect of DNA chemistry The concept of phosphoramidite chemistry for automated solid‐phase synthesis (SPS) of DNA as first described by Caruthers in 1981 [2] has on the whole remained unaltered as it has proven to be a most versatile approach In principle any diol can

Preface

xx Preface

be used for the stepwise build‐up of functional molecules as the concept is not restricted to nucleosides provided the other functional groups that are present are compatible with the strongly acidic basic and oxidising environment in SPS although milder conditions are also available In addition nucleosides can be chemically functionalised with almost any additional group be it small organic molecules or large metal complexes The combination of all accessible building blocks has lead to a system that is now being explored in almost all areas of science as mentioned earlier

The chapters in this book present an excellent collection of state‐of‐the‐art reviews covering research that is currently being carried out The chapters are devoted to the most important fields being studied

1 (Non‐) covalently modified DNA with novel functions2 DNA wires and electron transport through DNA3 Oligonucleotides in sensing and diagnostic applications4 Conjugation of DNA with biomolecules and nanoparticles5 Alternative DNA structures switches and nanomachines

Each chapter is devoted to a specialised topic within the larger context of DNA chemistry and will give the reader both an introduction to the field and the relevant technologies and a more focussed description of the authorsrsquo own research and viewpoint General conclusions and outlooks for the future are also given We are in the very lucky position of having been able to attract many of the key players in the relevant areas to devote their time to writing what we believe is an outstanding collection of well written and up‐to‐date chapters As the field is growing so rapidly it would be beyond the scope of any textbook to include everyone currently working in this field or to mention the excellent new ideas of every research group This demonstrates that applied DNA technology has reached the level at which it is playing a key role across the board

Nucleotide technology is a fast moving area where research is advancing rapidly However these chapters will certainly remain a key collection for some years to come Even though the systems will steadily improve the basic technologies presented and discussed here will remain the same for the foreseeable future as can be seen from the basic SPS principles The book is intended to give the novice an introduction and a basic overview of all aspects of nucleotide technology including strategies concepts and visions The experienced reader will have an up‐to‐date volume at hand where ndash through the amalgamation of very different ideas ndash novel applications and concepts may be conceived We are therefore convinced that this collection will be very useful to scientists at all levels and we hope that it will indeed trigger the emergence of new research

It is generally difficult if not impossible to predict where the future will take us as new results are being published on a daily basis sometimes in unrelated fields where the impact on onersquos own research may not be immediately evident Many of the approaches used today could not have been predicted ten years ago as some of the key technologies were not available then (eg DNA origami) DNA technology will continue to be important at both the giving and receiving ends DNA bio-nanotechnology will influence material medicinal and biological sciences whereas inventions and demands from those fields will have an impact on the direction of the development of DNA technology

We give great thanks to all contributors to this book and hope that the reader will enjoy it as much as we did during the editorial stages

Eugen StulzGuido H Clever

Preface xxi

References

[1] (a) R E Franklin and R G Gosling Molecular configuration in sodium thymonucleate Nature 1953 171 (4356) 740ndash741 (b) J D Watson and F H C Crick Molecular structure of nucleic acids A structure for deoxyribose nucleic acid Nature 1953 171 (4356) 737ndash738 (c) M H Wilkins A R Stokes and H R Wilson Molecular structure of nucleic acids Molecular structure of deoxypentose nucleic acids Nature 1953 171 (4356) 738ndash740

[2] (a) S L Beaucage and M H Caruthers Deoxynucleoside phosphoramidites ndash A new class of key intermediates for deoxypolynucleotide synthesis Tetrahedron Lett 1981 22 (20) 1859ndash1862 (b) M D Matteucci and M H and Caruthers Nucleotide Chemistry 4 Synthesis of deoxyoligonucleotides on a polymer support J Am Chem Soc 1981 103 (11) 3185ndash3191

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

xx Preface

be used for the stepwise build‐up of functional molecules as the concept is not restricted to nucleosides provided the other functional groups that are present are compatible with the strongly acidic basic and oxidising environment in SPS although milder conditions are also available In addition nucleosides can be chemically functionalised with almost any additional group be it small organic molecules or large metal complexes The combination of all accessible building blocks has lead to a system that is now being explored in almost all areas of science as mentioned earlier

The chapters in this book present an excellent collection of state‐of‐the‐art reviews covering research that is currently being carried out The chapters are devoted to the most important fields being studied

1 (Non‐) covalently modified DNA with novel functions2 DNA wires and electron transport through DNA3 Oligonucleotides in sensing and diagnostic applications4 Conjugation of DNA with biomolecules and nanoparticles5 Alternative DNA structures switches and nanomachines

Each chapter is devoted to a specialised topic within the larger context of DNA chemistry and will give the reader both an introduction to the field and the relevant technologies and a more focussed description of the authorsrsquo own research and viewpoint General conclusions and outlooks for the future are also given We are in the very lucky position of having been able to attract many of the key players in the relevant areas to devote their time to writing what we believe is an outstanding collection of well written and up‐to‐date chapters As the field is growing so rapidly it would be beyond the scope of any textbook to include everyone currently working in this field or to mention the excellent new ideas of every research group This demonstrates that applied DNA technology has reached the level at which it is playing a key role across the board

Nucleotide technology is a fast moving area where research is advancing rapidly However these chapters will certainly remain a key collection for some years to come Even though the systems will steadily improve the basic technologies presented and discussed here will remain the same for the foreseeable future as can be seen from the basic SPS principles The book is intended to give the novice an introduction and a basic overview of all aspects of nucleotide technology including strategies concepts and visions The experienced reader will have an up‐to‐date volume at hand where ndash through the amalgamation of very different ideas ndash novel applications and concepts may be conceived We are therefore convinced that this collection will be very useful to scientists at all levels and we hope that it will indeed trigger the emergence of new research

It is generally difficult if not impossible to predict where the future will take us as new results are being published on a daily basis sometimes in unrelated fields where the impact on onersquos own research may not be immediately evident Many of the approaches used today could not have been predicted ten years ago as some of the key technologies were not available then (eg DNA origami) DNA technology will continue to be important at both the giving and receiving ends DNA bio-nanotechnology will influence material medicinal and biological sciences whereas inventions and demands from those fields will have an impact on the direction of the development of DNA technology

We give great thanks to all contributors to this book and hope that the reader will enjoy it as much as we did during the editorial stages

Eugen StulzGuido H Clever

Preface xxi

References

[1] (a) R E Franklin and R G Gosling Molecular configuration in sodium thymonucleate Nature 1953 171 (4356) 740ndash741 (b) J D Watson and F H C Crick Molecular structure of nucleic acids A structure for deoxyribose nucleic acid Nature 1953 171 (4356) 737ndash738 (c) M H Wilkins A R Stokes and H R Wilson Molecular structure of nucleic acids Molecular structure of deoxypentose nucleic acids Nature 1953 171 (4356) 738ndash740

[2] (a) S L Beaucage and M H Caruthers Deoxynucleoside phosphoramidites ndash A new class of key intermediates for deoxypolynucleotide synthesis Tetrahedron Lett 1981 22 (20) 1859ndash1862 (b) M D Matteucci and M H and Caruthers Nucleotide Chemistry 4 Synthesis of deoxyoligonucleotides on a polymer support J Am Chem Soc 1981 103 (11) 3185ndash3191

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

Preface xxi

References

[1] (a) R E Franklin and R G Gosling Molecular configuration in sodium thymonucleate Nature 1953 171 (4356) 740ndash741 (b) J D Watson and F H C Crick Molecular structure of nucleic acids A structure for deoxyribose nucleic acid Nature 1953 171 (4356) 737ndash738 (c) M H Wilkins A R Stokes and H R Wilson Molecular structure of nucleic acids Molecular structure of deoxypentose nucleic acids Nature 1953 171 (4356) 738ndash740

[2] (a) S L Beaucage and M H Caruthers Deoxynucleoside phosphoramidites ndash A new class of key intermediates for deoxypolynucleotide synthesis Tetrahedron Lett 1981 22 (20) 1859ndash1862 (b) M D Matteucci and M H and Caruthers Nucleotide Chemistry 4 Synthesis of deoxyoligonucleotides on a polymer support J Am Chem Soc 1981 103 (11) 3185ndash3191

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

(Non‐) Covalently Modified DNA with Novel Functions

Part I

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

DNA in Supramolecular Chemistry and Nanotechnology First Edition Edited by Eugen Stulz and Guido H Clever copy 2015 John Wiley amp Sons Ltd Published 2015 by John Wiley amp Sons Ltd

Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK

Glenn A Burley

11DNA‐Based Construction of Molecular

Photonic Devices

111 Introduction

Controlling the spatial arrangement of photonic materials reproducibly and with nanoscale precision is of fundamental importance for the development of optoelectronic devices and sensors of the future Over the past 30 years industry has made phenomenal progress in the fabrication of optoelectronic circuits and devices with a high level of accuracy and reproducibility lsquoTop downrsquo nanolithography has been the major driver in these developments producing devices and circuits with resolution levels ranging from tens [1] to hundreds of nanometres [2] Top down photolithographic approaches such as Extreme Ultraviolet Lithography (EUV) have been the predominant methods used to fabricate optoelectronic devices with sub‐50 nm resolution lev-els One of the major drawbacks in the further development of higher resolution circuits fabricated using EUV is the rising cost of the equipment required to produce smaller devices with sub‐22 nm resolution [3] The more recent development of Nanoimprint Lithography (NIL) for example can replicate high‐resolution patterns as small as 24 nm and is one of the leading contenders for the fabrication of sub‐22 nm circuitry [1a] yet technological hurdles such as the defectivity and process variability of the resultant device platforms requires further development [4]

As a consequence of the increasing technological as well as economic challenges involved in fabricating devices through purely lithographic approaches alternative methods and strategies of fabrication are now being investigated from both a fundamental as well as an applied perspective [5] Building circuits and devices from functional molecular building blocks that is a lsquobottom up approachrsquo is a particularly attractive method for achieving molecular‐scale precision [6] There is increasing interest in using supramolecular

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

4 DNA in supramolecular chemistry and nanotechnology

assembly principles to form functional optoelectronic devices and sensors for device applications [7] yet despite a number of seminal advances in this area [8] a significant challenge still remains that of fabricating precisely defined and error‐free nanomaterials over micron‐scale surface areas with complete 3D control and sub‐nanometre resolution in a reproducible fashion de novo [9] In contrast Nature is astute at preparing micron‐scale self‐assembled nanostructures via the use of a template‐driven process to direct both the formation and the control of the growth of the overall nanostructure [10] For example the protein ferritin can be used as a template for the controlled biomineralisation of nanostructures [11] Peptides can also be programmed to assemble in nanostructures and even act as templates for the assembly of non‐natural func-tional materials however the ability to form bespoke functional materials is still restricted by our limited understanding of the rules that govern their self‐assembly [10]

Of the biomacromolecules available in Nature DNA molecules and their structural analogues have emerged as excellent templates to guide the synthesis [12] as well as the assembly of functional nanomateri-als from the lsquobottom uprsquo (Figure 111a) [13] By exploiting the predictable base‐pairing rules of DNA and

Figure 111 (a) WatsonndashCrick base‐pairing is used in Nature to store genetic information and in DNA nano-technology to direct the assembly of sophisticated multi‐dimensional nanostructures DNA analogues such as Peptide Nucleic Acids (PNA) have also been used to direct the assembly of DNA nanostructures (b) Schematic representation of DNA origami A single‐stranded DNA template is weaved in two‐ and three‐dimensional DNA nanostructures using a variety of oligodeoxyribonucleotide (ODN) staple strands (c) Triplex Forming Oligonucleotides (TFOs) offer an alternative directing modality through the formation of triplex structures

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

DNA‐based construction of molecular photonic devices 5

the high density of information embedded in its structure DNA‐programmed self‐assembly can form sophis-ticated multi‐dimensional assemblies ranging from 3D crystals [14] micron‐scale 2D [15] and 3D [15b 16] DNA nanostructures as well as dynamic nanostructures [17] which can be reconfigured to release a thera-peutic cargo in response to molecular cues [18]

The principal aim of this chapter is to highlight the recent developments in the use of DNA‐programmed self‐assembly to guide the construction of discrete photonic nanostructures The advantages and disadvan-tages of using DNA‐programmed self‐assembly to construct arrays of organic fluorophores and proteins will be presented The second half of the chapter will review efforts focusing on different modes of DNA‐pro-grammed self‐assembly to fabricate optoelectronic circuits and light‐harvesting complexes For specific applications of DNA‐directed assembly for the construction of supramolecular photosynthetic mimics the reader is directed to a recent review by Albinsson Hannestad and Boumlrjesson [19] DNA‐programmed assem-bly of metallic and semiconductor nanoparticles is another rapidly expanding area of DNA nanotechnology This has been the subject of recent reports and will not be discussed herein [13a 13c 20]

112 Using DNA as a template to construct discrete optoelectronic nanostructures

DNA is a unique self‐assembling molecular system This uniqueness arises from the inherent program-mability of WatsonndashCrick base‐pairing of Adenine (A) hydrogen‐bonding with Thymine (T) and Guanine (G) hydrogen‐bonding with Cytosine (C) [13b] Both the programmability and flexibility of these pairing rules can be used to form a variety of structures ranging from simple duplexes through to more complex four‐stranded Holliday junctions Further enhancement of the stiffness of DNA nanostructures is also possible as a consequence of the development of double and triple cross‐over motifs [13b] The high level of programmability of DNA is also underpinned by the availability of pre‐designed sequences ndash both short and long This is a key aspect of DNA nanotechnology and sets it apart from other self‐ assembling biomolecules as both short and long DNA sequences can be prepared and amplified to produce suitable amounts of the template for fundamental investigations For example solid‐phase syn-thesis can produce modified oligodeoxyribonucleotides (ODNs) up to ~120 nucleotides in length [21] whereas longer DNA sequences of up to 20 kilobases in length can be prepared using the Polymerase Chain Reaction (PCR) [22]

Taken collectively both the availability of material the predictability of self‐assembly rules and the more recent advent of computer software to facilitate the design of DNA nanostructures has spurred on the con-struction of sophisticated two‐ and three‐dimensional nanostructures One of the most successful exemplars of this has been lsquoDNA origamirsquo which weaves a long single‐stranded DNA template with the help of a series of shorter ODN strands (Figure 111b) [15a] Since modified ODNs with a precise functionalisation pattern can be prepared by solid‐phase synthesis the insertion of non‐natural functionality at precise locations in an origami‐design DNA‐programmed array can be realised [21 23] and has been used with great effect to template a vast array of functional materials along a DNA nanostructure [21 24]

Traditional strategies to construct DNA nanostructures have focused on utilizing WatsonndashCrick base pair-ing between two complementary DNA strands A less investigated strategy to control the addressability of optical functionality is to exploit the topological features of higher order DNA structures (Figure 112a) With its 2 nm diameter repetitive helicity of 34 nm arrangement of base‐pair lsquobitsrsquo of information every 034 nm and its widespread occurrence in DNA nanostructures B‐type double‐stranded DNA (dsDNA) offers an auxiliary mode to address optoelectronic materials For example the large surface area and solvent accessible major groove is the primary site for DNA‐binding domains found in Transcription Factors [25] Minor‐groove binding small molecules such as Hoechst 33258 (1) and DNA‐binding polyamides (PAs 2 Figure 112b) [26] offer an alternative mode of duplex DNA binding in the deep hydrophobic minor groove [27]

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)

6 DNA in supramolecular chemistry and nanotechnology

Tethering functionality to specific sites on these molecules can therefore be used to direct optoelectronic materials to a specific dsDNA sequences within nanostructures

Nucleic acid analogues such as Peptide Nucleic Acids (PNA) and Triplex Forming Oligonucleotides (TFOs) are another family of molecules that can bind to dsDNA in a sequence‐selective fashion PNA for example has a number of binding modes ranging from strand invasion of dsDNA through to triplex forma-tion (Figure 111a) [28] The different PNA binding modes are influenced by the DNA target sequence which allows one to develop binding strategies that are contextualised by sequence and the mode of binding In contrast TFOs form triplex structures with dsDNA via the recognition of the edges of WatsonndashCrick base‐pairs protruding into the major groove (Figure 111c) [29]

Finally more generic binding modes can also be exploited for binding to duplex DNA (Figure 112a) For example the hydrophobic interior of dsDNA enables aromatic and positively charged molecules such as cryptolepine (3) and YO‐PRO (4) which can intercalate between base‐pairs (Figure 112b) [30] Electrostatic interactions can also play an important role in templating functional materials The highly charged anionic phosphodiester backbone can be used to template a wide range of cationic polymers [31] and polyamines [32] through electrostatic attraction albeit in a non‐sequence specific manner Both of these modes do not possess the equivalent level of programmability of minor‐ or major‐groove binders however they do provide the potential to interface with DNA nanostructures in a more generic fashion if programmability is not an essen-tial requirement

Currently there are two major categories of DNA binding used to construct DNA‐programmed assemblies and arrays

i Construction of arrays that utilise single‐stranded DNA (ssDNA) as a template These multi‐chromophoric assemblies typically utilise modified ODNs and WatsonndashCrick base‐pairing to direct the construction of higher order supramolecular arrays [33]

ii Construction of arrays that utilise dsDNA as the template This strategy exploits the topological characteristics of DNA duplexes to place optoelectronic materials in precise locations along a DNA architecture These binding modes include the use of intercalators [34] and minor‐groove binding ligands [35] to direct positional assembly within DNA nanostructures

Figure 112 (a) Structure of a B‐type DNA duplex and the location of ligand binding (b) Representative subset of DNA minor‐groove binder (eg 1 and 2) and DNA intercalators (eg 3 and 4)