Molecular Modeling in the Undergraduate Curriculum.
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Transcript of 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
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
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
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
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
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
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
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