Molecular Modeling in
the Undergraduate
Curriculum
Molecular Modeling in the
Undergraduate Curriculum
Rebecca R. Conry
 Shari U. Dunham
 Stephen U. Dunham
 Margaret H. Hennessy
 D. Whitney King
 Julie T. Millard
 Bradford P. Mundy
 Dasan M. Thamattoor
 Thomas W. Shattuck

-Inorganic
-Biochemistry
-Biochemistry
-Physical
-Analytical
-Biochemistry
-Organic
-Organic
-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
C
Ene r gy ( k ca l/ mo l)
C
0 .0 2
C
C
C
C
C
Dihe d ra l E ne rg y ( k c a l/ m ol)
3
2
1
0 .0 1
re pulsio n
0 .0 0
-0 .0 1
-0 .0 2
-0 .0 3
at t r act ion
-0 .0 4
-0 .0 5
2.0
3 .0
4 .0
H. . . H di st a nce ( Å)
0
0
100
200
D ihe d ra l A ngl e
300
5 .0
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 acid
H7 -
O1 -
O3 |
P2
| \\
H6
H4
O5
Atomic Charges and Dipole Moment
O1 charge=-0.594
P2 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
OrganuLa tOr Organic Calculator
O
O
CH3CH2COCH3+* +
2-butanone+*
+
O
—> CH3CO+
+ CH3CH2*
—> methyl acylium+
+ ethyl*
135.06 kJ/mol
C1-3
C4-6
O Molecules
O,C1-3
O Radical Cations O-C4-5
O Radicals
O=C4-5
O Cations
Nitrogen
O Anions
Halogens
Inorganic
O
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:  cyclodextrin
OH
O
O
HO
OH
O
HO
OH
OH
O
O
HO
HO
OH
O
O
HO
O
HO
HO
HO
O
OH
HO
HO
HO
O
O
HO O
HO
HO
O
OH
O
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
[F,Cl,Br,I]
» Halogen substituted
aromatic and a
carboxyl group
O
O
2D Substructure Searches
Cl

Query:
Cl
O
» Halogen substituted
aromatic and a
carboxyl group
O
O
O
N
O
O
N
O
N
F
O
I
N
N
O
N
F
F
O
3D Substructure Searches
A



Spatial
Relationships
Define ranges for
distances and
angles
Stored conformation
O(s1)
C (u)
O(s1)
3.3 - 4.3 Å
O
6.8 - 7.8 Å
» usually lowest energy
3.6 - 4.6 Å
[O,S]
A
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
3.2Å
Cl
O H
Cl
4.3Å
O H
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

ENZYME
Monoamine oxidase A
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.)
BLASTp
Monoamine 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