EMBO-Course
"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
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)
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program2004.09.10.pdf
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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.
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(The Movies is unavailabled during Mar.5,2009 to Mar.6,2009)
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Download File: practical.tar
Sept. 14:
Bert de Groot, Phil Biggin
MD Simulation with Gromacs |
Document |
Sept. 15:
Daan van Aalten
MD for drug design (Gromacs) |
Document |
Sept. 16:
Bert de Groot, Phil Biggin
Membrane protein simulations |
Document |
Sept. 18:
Jianpeng Ma
Normal mode analysis
|
Document |
Sept. 21:
Martin Stahl
Conformational analyses with the CSD |
Document |
Sept. 22:
Qi Chen
Docking and scoring
|
Document |
Sept. 23:
Jonathan Essex
Flexible docking
|
Document |
Sept. 24:
Gerrit Groenhof
Hybrid QM/MM (Gromacs)
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Document |
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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
http://www.dddc.ac.cn
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Updated
03/05/2009
, Frauke
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