Molecular Modeling in the Undergraduate Curriculum

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Molecular Modeling in the Undergraduate Curriculum
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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

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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

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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

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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

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When, Where, How

• Classroom
• Laboratory
• Homework
• Projects
• Tests
• Thesis

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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

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General Chemistry

• Potential Energy Functions
• Torsional and Van der Waals

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General Chemistry

• Molecular Mechanics
• Hyroxyl Group
• H2O2, Methanol, Amino Acids
• Catalase, Alcohol Dehydrogenase
• Insight/CHARMm
• Molecular Orbital Theory
• O2 MOs (Sontum, Walstrum,
  Jewett)
• Electrostatic Distributions (Shusterman)
• Spartan

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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

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Molecular Structure Calculations
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Organic Radical Cations, Neutral Radicals,
Cations, and Anions
ethyl
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Organic Chemistry

• Electrostatic distribution

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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

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Organic Chemistry

• Bridgehead alkenes and cations

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Physical Chemistry

• Molecular Mechanics
• Insight/CHARMm, MM2
• Molecular dynamics
• Free Energy Perturbation Theory
• solvation
• binding eguilibrium
• Molecular Orbital Theory
• Spartan, MOPAC, Gaussian

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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 nOes

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Distance Geometry

• NMR Constraints, nOe distances
• Hydrogen bonding constraints
• Generate 3D structure
• 2D-gt3D conversion
• Follow with Molecular Mechanics
• EMBED G. Crippen, I. Kuntz, T. Nordland, T.
  Havel, UCSF
• JavaMolecularEditor, Peter Ertl at Novartis

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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

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Computer Aided Molecular Design

• A Strategy for Meeting the Challenges We Face

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An Organized Guide

• Build Chemical Insight
• Discover new molecules
• Predict their properties

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Principles

• Structure-Function Relationships
• Binding
• Understand and control binding -gtdisease
• Molecular Recognition
• How do enzymes recognize and bind the proper
  substrates
• Guest-Host Chemistry
• Molecular Recognition in Cyclodextrins

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Hosts ?? cyclodextrin
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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

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Binding Site Model

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

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Structure Searches

• 2D Substructure searches
• 3D Substructure searches
• 3D Conformationally flexible searches
• cfs

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2D Substructure Searches

• Functional groups
• Connectivity
• Halogen substituted aromatic and a carboxyl group

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2D Substructure Searches

• Query
• Halogen substituted aromatic and a carboxyl group

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3D Substructure Searches

• Spatial Relationships
• Define ranges for distances and angles
• Stored conformation
• usually lowest energy

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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

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Acetylcholine Esterase

• Neurotransmitter recycling
• Design drug that acts like nicotinamide

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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

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Estimating log P

• M (aq) gt M (octanol) ?PG -RT ln P
• M (aq) gt M (g) ?desolG(aq)
• M (octanol) gt M (g) ?desolG(octanol)
• ?PG ?desolG(aq) ?desolG(octanol)
• ?PG Fh2o - Foct
• log P (1/2.303RT) Fh2o - Foct
• 1/2.303RT 0.735

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Biochemistry- Lysozyme
CASTp pocket identification
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Biochemistry

• Conformational Energetics of Oligosaccharides
• Stereospecificity of Lactate Dehydrogenase
  Isozymes
• Bioinformatics
• Homology Modeling

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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.)
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BLASTpMonoamine Oxidase A
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Homology Modeling Lactate Dehydrogenase Isozymes
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Synthesis- Reaction Databases

• 600,000 organic reactions
• Synthetic routes
• ChemInform - Reacts, ISIS/Host
• Access by substructure and bond rearrangments
• Most used database by students

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High Throughput Screening

• Test 10,000-100,000s of compounds
• Robotics
• Individually tested
• Pfizer gt 250,000 compound library
• Combinatorial Chemistry
• Parallel testing
• Cleverly prepared mixtures
• Recover most active compounds

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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

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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