"Methods for protein simulations and drug design"

Mon, 13/09/2004 - Fri, 24/09/2004

Drug Discovery and Design Center (DDDC)

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai

Topics & Teachers || Schedule || Teaching Materials || Lectures || Practicals || Photoes / DVs || Contact || DDDC home

Topics & Teachers

Molecular dynamics simulations:

  • Essential dynamics for large-scale domain motions
  • Simulations of membrane proteins
  • Protein dynamical transition
  • MD for docking
  • Implicit solvent models

    Computer-aided drug design:

  • Including protein flexibility into docking schemes
  • Free energy calculation: perturbation methods
  • Empirical scoring functions, virtual screening
  • active site prediction and modelling

    Quantum mechanical methods for protein simulations:

  • Car-Parrinello Molecular Dynamics
  • Combined quantum/molecular mechanics
  • QM/MM for drug design

    Teachers (c:confirmed)

  • Jeremy Smith, Biocomputing, University of Heidelberg (c)
  • Wilfried van Gunsteren, IGC, ETH Zürich (c)
  • Bert de Groot, MPI for Biophysical Chemistry, Göttingen (c)
  • Phil Biggin, Molecular Biophysics, University of Oxford (c)
  • Jianpeng Ma, Baylor College of Medicine, Houston (c)
  • Daan van Aalten, Drug Design, University of Dundee (c)
  • Johan Åqvist, Cell and Mol. Biology, University of Uppsala (c)
  • Jonathan Essex, University of Southampton (c)
  • Martin Stahl, Roche, Basel (c)
  • William N. Lipscomb, Harvard University (c)
  • Qi Chen, Lilly Research Leboratories, Indianapolis (c)
  • Gerhard Klebe, Drug Design, University of Marburg (c)
  • Ursula Roethlisberger, University of Lausanne (c)
  • Gerrit Groenhof, University of Groningen (c)





    Teaching Materials

    Module I: Molecular Dynamics

    Membrane protein simulations, Phil Biggin

  • "Molcular Modelling. Principles and Applications". Andrew Leach. Publisher: Prentice Hall. ISBN: 0582382106. This book has rapidly become the defacto introductory text for all aspects of simulation.
  • "Molecular Dynamics Simulation: Elementary Methods". J.M. Haile. Publisher: Wiley. ISBN: 047118439X. This text provides a more focus but slightly more old-fashioned view of simulation. It has some nice simple examples of how to code (in fortran) some of the algorithms though.
  • "Membrane Protein Structure: Experimental Approaches". Stephen White (Ed). Publisher: OUP. ISBN: 0196071123. This text has good introductory chapters from leading experimentalists in the field.
  • "Membrane Protein Dynamics versus Environment: Simulations of OmpA in a Micelle and in a bilayer." Bond, P.J. and Sansom, M.S.P. JMB (2003) 329 1035-1053. The same protein as in this practical but analysed in the context of different environments. pdf
  • "The simulation approach to bacterial outer membrane proteins". Bond, P.J and Sansom, M.S.P. Mol Membr Biol. 2004. 3. 151-161 A recent review discussing simulations of outer-membrane proteins. pdf
  • "Potassium channel, ions, and water: simulation studies based on the high resolution X-ray structure of KcsA". Domene, C. and Sansom, M.S.P. Biophys J. 2003. 85. 2787-2800. pdf
  • "A microscopic view of ion conduction through the K+ channel". Berneche, S. and Roux, B. Proc Natl Acad Sci U S A. 2003 100(15):8644-8648. Detailed analysis of ion permeation. pdf

    Molecular Dynamics for Drug Design, Daan van Aalten

  • Visit the Prodrug Server at http://davapc1.bioch.dundee..ac.uk/prodrg
  • Crystal Structure of Carboxypeptidase A Complexed with D-Cysteine at 1..75 A - Inhibitor-Induced Conformational Changes, Daan M. F. van Aalten, Curtis R. Chong, and Leemor Joshua-Tor Biochemistry 2000, 39, 10082-10089 pdf
  • Protein Dynamics Derived form Clusters of Crystal Structures, D.M.F. van Aalten et al, Biophysical Journal, Vol. 73, 1997, 2891ff pdf
  • Interactions of LY333531 and Other Bisindolyl Maleimide Inhibitors with PDK1, D. Komander et al, Structure, Vol. 12, 215?26, February, 2004,pdf
  • PRODRG: a tool for high-throughput crystallography of proteinħligand complexes, Alexander W. Schuettelkopf and Daan M. F. van Aalten, Acta Crystallographica Section D Biological Crystallography pdf

    Binding pockets, Gerhard Klebe

  • From Structure to Function: A New Approach to Detect Functional Similarity among Proteins Independent from Sequence and Fold Homology Stefan Schmitt, Manfred Hendlich, and Gerhard Klebe, Angew. Chem. Int. Ed. 2001, 40, No. 17 pdf
  • A New Method to Detect Related Function Among Proteins Independent of Sequence and Fold Homology Stefan Schmitt1,2, Daniel Kuhn1 and Gerhard Klebe1* J. Mol. Biol. (2002) 323, 387?06 pdf
  • Predicting binding modes, binding affinities and `hot spots' for protein-ligand complexes using a knowledge-based scoring function HOLGER GOHLKE, MANFRED HENDLICH and GERHARD KLEBE Perspectives in Drug Discovery and Design, 20: 115?44, 2000. pdf
  • Utilising Structural Knowledge in Drug Design Strategies: Applications Using Relibase Judith Gu ?nther1, Andreas Bergner2, Manfred Hendlich1 and Gerhard Klebe1* J. Mol. Biol. (2003) 326, 621?36 pdf
  • Virtual Screening for Submicromolar Leads of tRNA-guanine Transglycosylase Based on a New Unexpected Binding Mode Detected by Crystal Structure Analysis Ruth Brenk, Lars Naerum,,?Ulrich Gra¨dler,,| Hans-Dieter Gerber, George A. Garcia, Klaus Reuter, Milton T. Stubbs, and Gerhard Klebe*, J. Med. Chem. 2003. pdf
  • Flexible Adaptations in the Structure ofthe tRNA-Modifying Enzyme tRNA ?Guanine Trans- glycosylase and Their Implications for Substrate Selectivity, Reaction Mechanism and Structure- Based Drug Design Ruth Brenk, Milton T. Stubbs, Andreas Heine, Klaus Reuter, and Gerhard Klebe*[a] ChemBioChem 2003, 4, 1066 ?1077 pdf

    Normal mode analysis with CHARMM, Jianpeng Ma

  • J. Comput. Chem. Vol.16, 1522 (1995).
  • J. Mol. Biol. Vol.181, 423 (1985).
  • J. Comput. Chem. Vol.4, 187 (1983).

    Module II: Drug Design

    Free energy calculation, Johan Åqvist

  • Brandsdal B. O., Oesterberg F., Almloef M., Feierberg I., Luzhkov V. B., Åqvist J. Advances in Protein Chemistry (2003), 66: 123-158. Most useful for the lecture: first 4 chapters. pdf

    Docking methods, Qi Chen

  • the lecture for download EMBO040921.ppt
  • an extensive list of references EMBO040921_references.doc

    Protein flexibility and docking, Jon Essex

    For the practical:
  • FDS: R.D. Taylor, P.J. Jewsbury, J.W. Essex J. Comput. Chem. 24, 1637 (2003)
  • RESP : C. I. Bayly , P. Cieplak, W. D. Cornell and P. A. Kollman - J. Phys. Chem., 97, 10269 (1993)
  • AM1-BCC : A. Jakalian, B. L. Bush, D. B. Jack and C. I. Bayly - J. Comput. Chem., 21, 132 (2000)
  • AM1-BCC : A. Jakalian, D. B. Jack and C. I. Bayly - J. Comput. Chem., 23, 1623 (2002)
  • GB/SA : A. Leach - Molecular Modelling Principles and Application, entries on "continuum models"
  • empirical force field : same, entries on "force field models, empirical"
    For the lecture:
  • Docking review: R.D. Taylor, P.J. Jewsbury, J.W. Essex J. Comput. Aided Mol. Design 16, 151 (2002)
  • flexible protein docking review: H.A. Carlson Curr. Opin. Chemical Biology 6, 447 (2002)
  • Protein flexibility and drug design: S.J. Teague Nature Reviews Drug Discovery 2, 527 (2003)
  • Flexibility in protein-protein binding: C.-S. Goh, D. Milburn, M. Gerstein Curr. Opin. Structural Biology 14, 104 (2004)

    Similarity Searching, Martin Stahl

    General Reading

  • Willett, P. Chemical similarity searching. J. Chem. Inf. Comput. Sci. 1998, 38, 983-996.pdf
  • Sheridan, R. P.; Kearsley, S. K. Why do we need so many chemical similarity search methods? Drug Discovery Today 2002, 7, 903-911.pdf

    Virtual Screening

  • Stahl, M.; Rarey, M.; Klebe, G. Screening of drug databases. Bioinformatics: From Genomes to Drugs; VCH: Weinheim, 2002; pp 229-264.pdf
  • Raymond, J. W.; Willett, P. Effectiveness of graph-based and fingerprint-based similarity measures for virtual screening of 2D chemical structure databases. J. Comput.-Aided Mol. Design 2002, 16, 59-71.pdf

    Bit string methods

  • Martin, Y. C.; Kofron, J. L.; Traphagen, L. M. Do structurally similar molecules have similar biological activity? J. Med. Chem. 2002, 45, 4350-4358.pdf
  • Flower, D. R. On the properties of bit string measures of chemical similarity. J. Chem. Inf. Comput. Sci. 1998, 38, 379-386.pdf

    Conformational Analysis using the CSD, Martin Stahl

    General Reading:

  • Respective sections in standard organic chemistry textbooks on conformational properties of open-chain and cyclic hydrocarbons, anomeric effect etc. Hoffmann, R. W.; Stahl, M.; Schopfer, U.; Frenking, G. Conformation design of hydrocarbon backbones. Chem. Eur. J. 1998, 4, 559-566.pdf

    Applications of the CSD

  • Taylor, R. Life-science applications of the Cambridge structural database. Acta Cryst. 2002, D58, 879-888.pdf
  • Klebe, G.; Mietzner, T. A fast and efficient method to generate biologically relevant conformations. J. Comput.-Aided Mol. Design 1994, 8, 583-606..pdf

    Module III: QM/MM

    QM/MM with Gromacs, Gerrit Groenhof

  • Basic course in physical chemistry, e.g. P.W. Atkins Physical Chemistry (any edition) Chapters 11-14)
  • General reading about Quantum Chemistry:
    Attila Szabo and Neil S. Ostlund Modern quantum chemistry: introduction to advanced electronic structure theory.
    A good general text book on Quantum Chemistry. Reading this book is not a prerequisite for this course, it merely provides background material for a major part of the course. For derivations etc. I will refer to this book occasionally.
  • General reading about QM/MM:
    Kirsten P. Eurenius, David C. Chatfield, Bernard R. Brooks, and Milan Hodoscek Enzyme mechanisms with hybrid quantum and molecular mechanical potentials. I. Theoretical considerations. International Journal of Quantum Chemistry Volume 60, Issue 6 , Pages 1189 - 1200
    This short review paper gives a nice overview of all aspects of a QM/MM calculation.
  • Application of QM/MM to Photoactive Yellow Protein
    G. Groenhof, M. Bouxin-Cademartory, B. Hess, S.P. de Visser, H.J.C. Berendsen, M. Olivucci, A.E. Mark and M.A. Robb. Photoactivation of the Photoactive Yellow Protein: Why photon absorption triggers a trans-to-cis isomerization of the chromophore in the protein. Journal of the American Chemical Society, 126 (2004), 4228-4233.
    This paper provides an example of how QM/MM aproaches can be used for studying the functions of proteins. The paper will be discussed in detail in one of the lectures.

    Please check regularly for udpdates.



    Sept. 13:
    Jeremy Smith
    Introduction to protein simulations and drug design
    Sept. 14:
    Bert de Groot, Phil Biggin
    Introduction to molecular dynamics simulations
    URL embo-2004-09-14-Groot.wmv
    Sept. 15:
    Daan van Aalten
    MD for drug design
    URL embo-2004-09-15-Daan-a.WMV
    Gerhard Klebe
    Prediction of active sites


    Sept. 16:
    Jeremy Smith
    Protein dynamics and function, Protein dynamical transition
    Phil Biggin,Bert de Groot
    Membrane protein simulations
    Sept. 17:
    Phil Biggin
    Bert de Groot
    Essential dynamics
    URL embo-2004-09-17-Groot-b.WMV
    Jianpeng Ma
    Normal mode analysis
    zipped, 9.27M embo-2004-09-17-jianpengma-a.WMV
    Wilfried van Gunstere
    Validating MD simulations through comparison with experimental data
    zipped, 9.27M embo-2004-09-17-Grunsteren-b.WMV
    Sept. 20:
    Johan Aqvist
    Free energy calculation: FEP, LIE
    Martin Stahl
    Conformational analyses with the Cambridge Structural Database (CSD)
    Sept. 21:
    Qi Chen
    Docking and scoring
    Martin Stahl
    Similarity search
    Sept. 22:
    Jonathan Essex
    Flexible docking
    William N. Lipscomb
    Drug design for diabetes type II
    Sept. 23:
    Gerrit Groenhof
    Hybrid QM/MM simulations with Gromacs, QM/MM application
    (zipped, 24M) embo-2004-09-24-gerrit-a.WMV
    Sept. 24:
    Ursula Roehtlisberger
    CPMD basics, CPMD for enzymatic reactions
    (zipped,24M) embo-2004-09-24-Ursola-a.wmv



    Download File: practical.tar

    Sept. 14:
    Bert de Groot, Phil Biggin
    MD Simulation with Gromacs
    Sept. 15:
    Daan van Aalten
    MD for drug design (Gromacs)
    Sept. 16:
    Bert de Groot, Phil Biggin
    Membrane protein simulations
    Sept. 18:
    Jianpeng Ma
    Normal mode analysis
    Sept. 21:
    Martin Stahl
    Conformational analyses with the CSD
    Sept. 22:
    Qi Chen
    Docking and scoring
    Sept. 23:
    Jonathan Essex
    Flexible docking
    Sept. 24:
    Gerrit Groenhof
    Hybrid QM/MM (Gromacs)



  • Frauke Meyer

    Tel: +86 21 50806600*1201

    Prof. Hualiang Jiang

    Tel: +86 21 50806600*1210

    Drug Discovery and Design Center,
    Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park
    Shanghai 201203
    Fax: +86-21-50807188


    Updated 03/05/2009 , Frauke