2011 AMS-535 Fall

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Current Announcements

  • Posted on 11/07/2011 by Lingling
  1. The average score for quiz III is 18.8 out of 25. If you need any help with the problems in the quiz, feel free to make an appointment with me and discuss about them.

  • Posted on 10/06/2011 by Lingling
  1. The PPT slides for the recent presentations have been uploaded
  2. Quiz 2 is 10/12, next Wednesday. Please be prepared.

  • Posted on 10/03/2011 by Lingling
  1. The average score for quiz I is 20.04out of 25. If you need any help with the problems in the quiz, feel free to make an appointment with me and discuss about them.
  2. Students who presented should email me the three quiz questions (one simple, one medium and one hard).

  • Posted on 09/20/2011 by Lingling
  1. I updated the presentation schedule for this semester. If you have any problems on your assigned topic/date, you need to let me know as soon as possible. Missing the presentation will affect your grades for the course.
  2. The slides for the students' presentation will usually be updated a few days before the actual presentation is given. The ones that are online now are examples from last year. Please check the dates on the slides to make sure that you are printing/downloading the newest version.
  3. Please email me your ppt slides and three questions on your topic (one hard, one medium, one easy; with your answers to the questions) at least one day before your presentation.
  4. Feel free to discuss your assigned topics with Rizzo lab members.
  5. The first quiz is going to be next Monday (09/26/2011). Please be prepared. The quiz will be based on lecture slides and class discussions.
  • Posted on 08/15/2011 by Lingling

Example Quiz/Exam Questions from Prior Semesters

Course Participants, Topics, References, and Schedule

  • Please note that a doctors excuse will be required if you miss a test or your scheduled oral presentation date because of illness.

Speaker and Presentation
Primary Reference
Secondary Reference
2011.08.29 Mon
  • No class: Hurricane Irene
2011.08.31 Wed
  • Organizational Meeting
2011.09.05 Mon
  • No Class: Labor Day
2011.09.07 Wed


  • Drug Discovery
  1. Introduction, history, irrational vs. rational
  2. Viral Target Examples
Rizzo, R.

1. Jorgensen, W.L., The many roles of computation in drug discovery. Science 2004, 303, 1813-8

2. Kuntz, I. D., Structure-based strategies for drug design and discovery. Science 1992, 257, 1078-1082

2011.09.12 Mon
  • Chemistry Review
  1. Molecular structure, bonding, graphical representations
  2. Functionality, properties of organic molecules
Rizzo, R.
2011.09.14 Wed
  • Biomolecular Structure
  1. Lipids, carbohydrates
  2. Nucleic acids, proteins
Rizzo, R.
structures of the 20 amino acid side chains
2011.09.19 Mon
  • Molecular Interactions and Recognition
  1. Electrostastics, VDW interactions, hydrophobic effect, molecular recognition (binding energy)
  2. Inhibitors types: allosteric, transition state, covalent vs non-covalent, selective, competitive
Rizzo, R.
2011.09.21 Wed
  • Intro. to Methods in 3-D Structure Determination
  1. Crystallography, NMR
  2. Structure Quality, PDB in detail
Rizzo, R.
2011.09.26 Mon
Quiz Prior Section I


  • Classical Force Fields
  1. All-atom Molecular Mechanics

Guest Lecture

Balius, T.

1. Mackerell, A. D., Jr., Empirical force fields for biological macromolecules: overview and issues. J. Comput. Chem. 2004, 25, 1584-604

1. van Gunsteren, W. F.; et al., Biomolecular modeling: Goals, problems, perspectives. Angew. Chem. Int. Ed. Engl. 2006, 45, 4064-92

2011.09.28 Wed
  • No Class: Follow a Friday Schedule
2011.10.03 Mon
  1. OPLS
  2. AMBER

1. Gan, Q.

2. Boyd, R.

1. Jorgensen, W. L.; et al., Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids. J. Am. Chem. Soc. 1996, 118, 11225-11236

2. Cornell, W. D.; et al., A Second Generation Force Field For the Simulation of Proteins, Nucleic Acids, and Organic Molecules. J. Am. Chem. Soc. 1995, 117, 5179-5197

1. Jorgensen, W. L.; et al., The Opls Potential Functions For Proteins - Energy Minimizations For Crystals of Cyclic-Peptides and Crambin. J. Am. Chem. Soc. 1988, 110, 1657-1671

2. Bayly, C. I.; et al., A Well-Behaved Electrostatic Potential Based Method Using Charge Restraints For Deriving Atomic Charges - the RESP Model. J. Phys. Chem. 1993, 97, 10269-10280

2011.10.05 Wed
  • Explicit Solvent Models
  1. Water models (TIP3P, TIP4P, SPC)
  2. Condensed-phase calculations (DGhydration)

1. Adewale, B.

2. Choi,W.

1. Jorgensen, W. L.; et al., Comparison of Simple Potential Functions for Simulating Liquid Water. J. Chem. Phys. 1983, 79, 926-935

2. Jorgensen, W. L.; et al., Monte Carlo Simulation of Differences in Free Energies of Hydration. J. Chem. Phys. 1985, 83, 3050-3054

2011.10.10 Mon
  • Continuum Solvent Models
  1. Generalized Born Surface Area (GBSA)
  2. Poisson-Boltzmann Surface Area (PBSA)

1. Hwang, G.

2. Groeneveld, K.

1. Still, W. C.; et al., Semianalytical Treatment of Solvation for Molecular Mechanics and Dynamics. J. Am. Chem. Soc 1990, 112, 6127-6129

2. Sitkoff, D.; et al., Accurate Calculation of Hydration Free Energies Using Macroscopic Solvent Models. J. Phys. Chem. 1994, 98, 1978-1988

2011.10.12 Wed
Quiz Prior Section II


  • Molecular Conformation
  1. Small molecules, peptides, relative energy, minimization methods

1. Kazi, R.

1. Howard, A. E.; Kollman, P. A., An analysis of current methodologies for conformational searching of complex molecules. J. Med. Chem. 1988, 31, 1669-75

1. Section 4 (PAGES 22-27) Colby College Molecular Mechanics Tutorial Introduction, 2004, Shattuck, T.W., Colby College

1. Holloway, M. K., A priori prediction of ligand affinity by energy minimization. Perspect. Drug Discov. Design 1998, 9-11, 63-84

2011.10.17 Mon
  • Primary Sampling Methods for Computer Simulations
  1. Molecular dynamics (MD)
  2. Monte Carlo (MC)

1. Chen,J.

2. Kim, E

1. Karplus, M.; Petsko, G. A., Molecular dynamics simulations in biology. Nature 1990, 347, 631-9

2. Metropolis Monte Carlo Simulation Tutorial, LearningFromTheWeb.net, Accessed Oct 2008, Luke, B.

2. Jorgensen, W. L.; TiradoRives, J., Monte Carlo vs Molecular Dynamics for Conformational Sampling. J. Phys. Chem. 1996, 100,14508-14513

2. Metropolis, N.;et al., Equation of State Calculations by Fast Computing Machines. The Journal of Chemical Physics 1953, 21, 1087-1092

2011.10.19 Wed
  • Predicting Protein Structure I.
  1. Ab initio prediction (protein-folding)
  2. Example Trp-cage

1. Klaritch-Vrana, B.

2. Lazo, E.

1. Dill, K. A.; Chan, H. S., From Levinthal to pathways to funnels. Nat. Struct. Biol. 1997, 4, 10-19

2. Simmerling, C.;et al., All-atom structure prediction and folding simulations of a stable protein. J. Am. Chem. Soc. 2002, 124,11258-9

1-2. Daggett, V.; Fersht, A., The present view of the mechanism of protein folding. Nat. Rev. Mol. Cell Biol. 2003, 4, 497-502

2011.10.24 Mon
  • Predicting Protein Structure II.
  1. Comparative (homology) modeling
  2. Case studies (CASP)

1.Guest Lecture


2. Santa Cruz, A.

1. Marti-Renom, M. A.; et al., Comparative protein structure modeling of genes and genomes. Annu. Rev. Biophys. Biomol. Struct. 2000,29,291-325

2. Moult, J., A decade of CASP: progress, bottlenecks and prognosis in protein structure prediction. Curr. Opin. Struct. Biol. 2005,15, 285-9

1. Fiser, A.; et al., Evolution and physics in comparative protein structure modeling. Acc. Chem. Res. 2002, 35, 413-21

2. Kryshtafovych, A.; et al., Progress over the first decade of CASP experiments. Proteins 2005, 61 Suppl 7, 225-36

2011.10.26 Wed
  • Enhanced Sampling Techniques
  1. Simulated annealing
  2. Protein Design

1.Guja, K.

2.Guest Lecture

Au, L.

1. Brunger, A. T.;Adams, P. D., Molecular dynamics applied to X-ray structure refinement. Acc. Chem. Res. 2002, 35, 404-12

2. Street, A. G.; Mayo, S. L., Computational protein design. Structure. 1999, 7, 105-9

1. Adams, P. D.; et al., Extending the limits of molecular replacement through combined simulated annealing and maximum-likelihood refinement. Acta Crystallogr D Biol Crystallogr 1999, 55, 181-90

2. Lippow, S. M.; Tidor, B., Progress in computational protein design. Curr. Opin. Biotechnol. 2007, 18, 305-311

2011.10.31 Mon
Quiz Prior Section III


  • Docking I.
  1. Introduction to DOCK
  2. Introduction to Virtual Screening

Guest Lecture

Mukherjee, S.

1. Moustakas, D. T.; et al., Development and Validation of a Modular, Extensible Docking program: DOCK 5. J. Comput. Aided Mol. Des. 2006, 20, 601-619

2. Klebe, G.; et al., Virtual ligand screening: strategies, perspectives and limitations. Drug. Disc. Today. 2006, 11, 580-595

1. Ewing, T. J.; et al., DOCK 4.0: search strategies for automated molecular docking of flexible molecule databases. J. Comput. Aided Mol. Des. 2001, 15, 411-28

2011.11.02 Wed
  • Discovery Methods I.
  1. Hotspot probes (GRID)
  2. COMFA

1.Wei, L.

2. Shi, H.

1. Goodford, P. J., A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J. Med. Chem. 1985, 28, 849-57

2. Kubinyi, H., Encyclopedia of Computational Chemistry, Databases and Expert Systems Section, John Wiley & Sons, Ltd. 1998

1. Cramer, R. D.; Patterson, D. E.; Bunce, J. D., Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J. Am. Chem. Soc., 1988, 110, 5959-5967

2011.11.07 Mon
  • Discovery Methods II.
  1. Pharmacophores in drug design #1
  2. Pharmacophores in drug design #2

Guest Lecture Jiang, L.

1. Chang, C.; et al., Pharmacophore-based discovery of ligands for drug transporters. Advanced Drug Delivery Reviews 2006, 58, 1431-1450

2. Alvarez, J.; et al., Pharmacophore-Based Molecular Docking to Account for Ligand Flexibility. Proteins 2003, 51, 172-188

2011.11.09 Wed
  • Discovery Methods III.
  1. De novo design #1
  2. De novo design #2

Guest Lecture Allen, W.

1. Jorgensen, W.; et al., Efficient drug lead discovery and optimization. Acc. of Chem. Research 2009, 42 (6), 724-733

2. Pegg, S. C.; Haresco, J. J.; Kuntz, I. D., A genetic algorithm for structure-based de novo design. J Comput Aided Mol Des 2001, 15, 911-33

2011.11.14 Mon
  • Docking II.
  1. Test Sets (binding modes)
  2. Test Sets (virtual screening)

Guest Lecture

Mukherjee, S.

1. Mukherjee, S.; et al., Docking Validation Resources: Protein Family and Ligand Flexibility Experiments. J. Chem. Info. Model. 2010, 50, 1986-2000

2. Irwin, J. J.; Shoichet, B. K., ZINC--a free database of commercially available compounds for virtual screening. J. Chem. Inf. Model. 2005, 45, 177-82

1. The CCDC/Astex Test Set

2. ZINC Website at UCSF, Shoichet group

2011.11.16 Wed
  • Docking III.
  1. Database Enrichment
  2. Footprint-based scoring

1. Guest Lecture Balius, T.

1. Huang, N.; et al., Benchmarking Sets for Molecular Docking. J. Med. Chem. 2006, 49(23), 6789-6801

1. Balius, T.E.; et al., Implementation and Evaluation of a Docking-Rescoring Method Using Molecular Footprint Comparisons. J. Comput. Chem. 2011, 32, 2273-2289.

2011.11.21 Mon
Quiz Prior Section IV


  • Free Energy Perturbation (FEP)
  1. Thermolysin with two ligands

1. Sin, J.

1. Bash, P. A.; Singh, U. C.; Brown, F. K.; Langridge, R.; Kollman, P. A., Calculation of the relative change in binding free energy of a protein-inhibitor complex. Science 1987, 235, 574-6

1. Jorgensen, W. L., Free Energy Calculations: A Breakthrough for Modeling Organic Chemistry in Solution. Accounts Chem. Res. 1989, 22, 184-189

1. Kollman, P., Free Energy Calculations: Applications to Chemical and Biochemical Phenomena. Chem. Rev. 1993, 93, 2395-2417

2011.11.23 Wed
  • No Class: Thanksgiving US
2011.11.28 Mon
  • Thermodynamic integration
  1. H5N1 Avian influenza N1-PVR
  2. Intro to Molecular Mechanics Poisson-Boltzmann / Generalized Born Surface Area Methods

1. Guest Lecture Jiang, L.,

2. Guest Lecture Huang,Y.

1. Lawrenz, M.; et al., Independent-Trajectories Thermodynamic-Integration Free-Energy Changes for Biomolecular Systems: Determinants of H5N1 Avian Influenza Virus Neuraminidase Inhibition by Peramivir. J. Chem. Theory Comput. 2009, 5, 1106-1116

2. Kollman, P. A.; Massova, I.; Reyes, C.; Kuhn, B.; Huo, S. H.; Chong, L.; Lee, M.; Lee, T.; Duan, Y.; Wang, W.; Donini, O.; Cieplak, P.; Srinivasan, J.; Case, D. A.; Cheatham, T. E., Calculating structures and free energies of complex molecules: Combining molecular mechanics and continuum models. Accounts Chem. Res. 2000, 33, 889-897

2011.11.30 Wed
  • case studies
  1. TI and MM-GBSA
  2. HIVgp41

1. Sinayev, R.

2. Wong, A.

1. Cai, Y.; Schiffer, C. A.; Decomposing the Energetic Impact of Drug Resistant Mutations in HIV-1 Protease on Binding DRV. J. Chem. Theory Comput. 2010, 6, 1358-1368

2. Strockbine, B.; Rizzo, R. C., Binding of Anti-fusion Peptides with HIVgp41 from Molecular Dynamics Simulations: Quantitative Correlation with Experiment. Prot. Struct. Funct. Bioinformatics 2007, 63, 630-642

2011.12.05 Mon
  • Linear Response
  1. Intro to Linear Response (LR method)
  2. Inhibition of protein kinases (Extended LR method)

1. Xia, Y.

2. Yeasmin, R.

1. Aqvist, J.; Mowbray, S. L., Sugar recognition by a glucose/galactose receptor. Evaluation of binding energetics from molecular dynamics simulations. J Biol Chem 1995, 270, 9978-81

2. Tominaga, Y.; Jorgensen, W. L.; General model for estimation of the inhibition of protein kinases using Monte Carlo simulations. J. Med. Chem. 2004, 47, 2534-2549

2011.12.07 Wed
  • Properties of Known Drugs
  1. Lipinski Rule of Five
  2. ADME prediction

1. Yuan, X.

2. Zhou, Y.

1. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J., Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug. Deliv. Rev. 2001, 46, 3-26

2. Hou, T. J.; Xu, X. J.; ADME evaluation in drug discovery. J. Mol. Model, 2002, 8, 337-349

1. Lipinski, C. A., Chris Lipinski discusses life and chemistry after the Rule of Five. Drug. Discov. Today 2003, 8, 12-6

2. Hou, T. J.; Xu, X. J.; AMDE Evaluation in drug discovery 3. Modeling blood-brain barrier partitioning using simple molecular descriptors. J. Chem. Inf. Comput. Sci., 2003, 43, 2137-2152

2011.12.12 Mon
  • Follow a Wednesday schedule
  • Final Exam discussion.
  1. Final Exam Study Guide Handout

1. Jiang, L.

1. final_exam_study_guide

last day of class
2011.12.19 Mon
5:15-7:45 PM

Unless otherwise noted the Final will be given in our regular class room.