From Drug Design

to Self-assembling Materials

Ivan Coluzza

Proteins

A protein is made of a list of ~20 different types of amino acids

Proteins fold to thermodynamically stable structures at finite temperature called Native States

Design is the process of finding all sequences that can fold to a given configuration

http://xray.bmc.uu.se/~kurs/BiostrukfunkX2/practicals/practical_1/figs/peptide_bond.jpg

Folding vs DesignE =

!

ij

CijSij

E =

!

ij

C̄ijSijE =

!

ij

CijS̄ij

EN =

!

ij

C̄ijS̄ij

Folding Design

ADSVGCA......

Examples of caterpillar design - refolding

Lipoprotein (2K57)

C-Terminal domain of the Ribosomal Protein (1CTF)

Protein G (1PGB)Nuclear RNA export factor

(1OAI)Coluzza I., Plos ONE 10.1371/journal.pone.0020853 (2011)

Equatorial Region

Hydrophobic Trap

Hydrophilic Cage

~164

Å

GroEL/GroES Chaperonin

! !

Hydrophobic Hydrophilic Non-Native

Native State

2

3a

4b

4a

1

3b Trans refolding path Cis refolding path Shuttling

Chaperonin reaction pathway

Coluzza I., van der Vies S. M., Frenkel D. Biophysical Journal 90 (10): 3375-3381 (2006)

Artificial Protein

C 1 2

2.0 Ao

CC12

2.0 Ao

C

Hydrogen Bonds

Patchy-ParticlesHard Core Patch

Bond

Bianchi et al. Phys. Rev. Lett. (2006) vol. 97 (16) pp. 4

Patchy-Polymer structure space

a

b

c

1 Patch 2 Patches

Increasing interaction

range

Patchy polymersUnderstand protein folding and design

Structure Prediction Drug Design

Aggregation (Alzheimer) Chaperonin &

Folding under confinementProtein

Evolution

Macroscopic Folding

Direct conversion of simulations

results to experiments

Create a material design framework

AcknowledgementsChristoph Dellago

Cristos Likos

Barbara Capone

Peter van Oostrum

Ronald Zirbs

Erik Reimhult

Mark Miller

Michele Vendruscolo

Daan Frenkel

Angelo Cacciuto

Angel Orte

Maria Jose Ruedas

Saskia van der Vies

Francesco Sciortino

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Marie Curie Program for Intra-European Mobility Grants FP6