Molecular Modeling in the Undergraduate

Curriculum

Molecular Modeling in the Undergraduate Curriculum

Rebecca R. Conry -Inorganic Shari U. Dunham -Biochemistry Stephen U. Dunham -Biochemistry Margaret H. Hennessy -Physical D. Whitney King -Analytical Julie T. Millard -Biochemistry Bradford P. Mundy -Organic Dasan M. Thamattoor -Organic Thomas W. Shattuck -Physical

Acknowledgements

National Science Foundation 1993, 1996

Howard Hughes Medical Institute 1996, 2000

Paul J. Schupf Scientific Computing Center 1993,1996,1998

New England Consortium for Undergraduate Science Education 1998

Introduction-Molecular Modeling

Information Technology StereoVisualization - Molecular Perspective Build Insight to solve challenges Unified array of techniques Link lecture and laboratory Where, When, and How

When, Where, How?

Research focus Teaching and research boundaries blur Time is short: expertise and skills Research quality tools early Repeat Use Often Productive student research

When, Where, How

Classroom Laboratory Homework Projects Tests Thesis

Information Rich Curriculum

Massive amount of information Database technology Central to mission of the course Students are active participants

» Gathering and Assessing Quality Simulation and Prediction

General Chemistry

Potential Energy Functions Torsional and Van der Waals

C

C

C C C CC

C

C

C

C

C

300200100000

1

2

3

Dihedral Angle

Dih

ed

ral

Energ

y (

kcal/

mol)

5.04.03.02.02.0

H...H distance (Å)

En

erg

y (

kca

l/m

ol)

attraction

repulsion

-0.05

-0.04

-0.03

-0.02

-0.01

0.00

0.01

0.02

General Chemistry

Molecular Mechanics» Hyroxyl Group

» H2O2, Methanol, Amino Acids

» Catalase, Alcohol Dehydrogenase» Insight/CHARMm

Molecular Orbital Theory» O2 MO’s (Sontum, Walstrum, Jewett)

» Electrostatic Distributions (Shusterman)

» Spartan

Molecular Structure Calculations

800 careful calculations on small inorganics and organics

Density functional theory gets MO ordering right for diatomics

NBO analysis for best Lewis Structure» localized electron pair model» hybridization

Searchable Web database

Molecular Structure Calculations

H3PO3, Phosphorous acidO3 - H4|

H7 - O1 - P2| \\H6 O5

Atomic Charges and Dipole Moment

O1 charge=-0.594P2 charge= 0.828 with a dipole moment of 1.79430 Debye

Hybridization in the Best Lewis Structure

1. A bonding orbital for O1-P2 with 1.9871 electrons__has 77.77% O 1 character in a sp2.42 hybrid__has 22.23% P 2 character in a s0.90 p3 d0.09 hybrid

Organic Radical Cations, Neutral Radicals, Cations, and Anions

O rg a n u L

a t O r O r g a n i c C a l c u l a t o r

OOO OOO OOO OOO

C H 3 C H 2 C O C H 3 + * + — > C H 3 C O + + C H 3 C H 2 *

2 - b u t a n o n e + * + — > m e t h y l a c y l i u m + + e t h y l *

1 3 5 . 0 6 k J / m o l

C 1 - 3

C 4 - 6

O , C 1 - 3

O - C 4 - 5

O = C 4 - 5

N i t r o g e n

H a l o g e n s

I n o r g a n i c

OOO M o l e c u l e sOOO R a d i c a l C a t i o n sOOO R a d i c a l sOOO C a t i o n sOOO A n i o n s

ethyl*

Organic Chemistry

Electrostatic distribution

Organic Chemistry

Molecular Orbital Theory- Spartan» Dimethylhexanes- ring conformations» Stabilities of butyl cations» Electrostatic distribution in allyl ions

Independent Projects» Synthesis and computation component» reaction intermediates» isomer energies» Dilantin, Strawberry Aldehyde, Limonene

Organic Chemistry Bridgehead alkenes and cations

Physical Chemistry

Molecular Mechanics» Insight/CHARMm, MM2

Molecular dynamics Free Energy Perturbation Theory

» solvation» binding eguilibrium

Molecular Orbital Theory» Spartan, MOPAC, Gaussian

NMR and Distance Geometry

Beta-ionone side chain geometry T2 relaxation; COSY, NOESY 2D-NMR Molecular Mechanics Molecular Dynamics

» Correlate motion with relaxation times» Explore conformation space

Distance Geometry based on nOe’s

Distance Geometry

NMR Constraints, nOe distances Hydrogen bonding constraints Generate 3D structure 2D->3D conversion Follow with Molecular Mechanics

» EMBED: G. Crippen, I. Kuntz, T. Nordland, T. Havel, UCSF

» JavaMolecularEditor, Peter Ertl at Novartis

Gramicidin-S

Open ended student project secondary and tertiary structure COSY, NOESY 2D-NMR Molecular Mechanics, constrained by

nOe and hydrogen bonding constraints Molecular Dynamics

Computer Aided Molecular Design

A Strategy for Meeting the Challenges We Face

An Organized Guide

Build Chemical Insight Discover new molecules Predict their properties

Principles

Structure-Function Relationships Binding

» Understand and control binding ->disease Molecular Recognition

» How do enzymes recognize and bind the proper substrates

Guest-Host Chemistry» Molecular Recognition in Cyclodextrins

Hosts: cyclodextrinO

HO

O

OH

OH

O

HO

O

HO

OH

O

HO

OHO

OH

O

HOO HO

OH

O HO

O

HO

HO

O

HO

O

OH

HO

O

HO

OOH

HO

CAMD

Determine Structure of Guest or Host Build a model of binding site Search databases for new guests (or hosts) Dock new guests and binding sites Predict binding constants or activity Synthesize guests or hosts

Binding Site Model

Using experimental binding constants Build interaction model of binding site Use 3D database searching to find other

tight-binding guests

Structure Searches

2D Substructure searches 3D Substructure searches 3D Conformationally flexible searches

» cfs

2D Substructure Searches

Functional groups Connectivity

» Halogen substituted aromatic and a carboxyl group

[

F

,

C

l

,

B

r

,

I

]

O

O

2D Substructure Searches

Query:» Halogen substituted

aromatic and a carboxyl group

N

O

O

Cl

O

O

Cl

N

N

N

O

O

F

F

O

F

O

O

N

I

O

N

3D Substructure Searches

Spatial Relationships

Define ranges for distances and angles

Stored conformation» usually lowest energy

C

(

u

)

O

(

s

1

)

O

(

s

1

)

A

A

[

O

,

S

]

O

3.6 - 4.6 Å

3.3 - 4.3 Å

6.8 - 7.8 Å

Conformationally Flexible Searches

Rotate around all freely rotatable bonds

Many conformations Low energy penalty Get many more hits Guests adapt to

hosts and Hosts adapt to guests

O

Cl

H

O

Cl

H

3.2Å

4.3Å

Acetylcholine Esterase

Neurotransmitter recycling

Design drug that acts like nicotinamide

Descriptors, Cerius2

Molar Volume, Vm Surface area Rotatable Bonds, Rotbonds Molecular Polarizability, Mpol

» Ease of distortion of electron clouds» sum of Van der Waals A coefficients

Molecular Refractivity, MR» size and polarizability» local non-lipophilic interactions

Estimating log P

M (aq) –> M (octanol) PG = -RT ln P

M (aq) –> M (g) desolG(aq)

M (octanol) –> M (g) desolG(octanol)

PG = desolG(aq) – desolG(octanol)

PG = Fh2o - Foct log P = – (1/2.303RT) Fh2o - Foct

» 1/2.303RT = – 0.735

Biochemistry- Lysozyme

CASTp pocket identification

Biochemistry

Conformational Energetics of Oligosaccharides

Stereospecificity of Lactate Dehydrogenase Isozymes

Bioinformatics Homology Modeling

Search in ENZYME for: monoamine oxidase a

1.4.3.4 Amine oxidase (flavin-containing). (AN: Monoamine oxidase. Tyramine oxidase.

Tyraminase. Amine oxidase.

Adrenalin oxidase.)

ENZYME Monoamine oxidase A

BLASTpMonoamine Oxidase A

Homology Modeling Lactate Dehydrogenase

Isozymes

Synthesis- Reaction Databases

600,000 organic reactions Synthetic routes ChemInform - Reacts, ISIS/Host Access by substructure and bond

rearrangments Most used database by students

High Throughput Screening

Test 10,000-100,000’s of compounds Robotics

» Individually tested» Pfizer: > 250,000 compound library

Combinatorial Chemistry» Parallel testing» Cleverly prepared mixtures» Recover most active compounds

Proteomics

LC/MS - Bioinformatics Protein complement (30,000-60,000)

» Expression proteomics Localization within cell Protein interactions

» Interaction proteomics Database searching

» Sequence tag-TagIdent» MS/MS-Sequest

Making Room

Have no choice Student independent research expected

» job interviews» best grad schools

Student perceptions: teach more» enlivens classroom» relevant» build expertise

Wet/Lab Computational lab