M ETHODS IN MOLECULAR BIOLOGY

Transcription

1 M ETHODS IN MOLECULAR BIOLOGY Series Editor John M. Walker School of Life Sciences University of Hertfordshire Hatfield, Hertfordshire, AL10 9AB, UK For further volumes:

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3 Homology Modeling Methods and Protocols Edited by Andrew J.W. Orry Molsoft L.L.C., San Diego, CA, USA Ruben Abagyan Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA; San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA, USA

4 Editors Andrew J.W. Orry, Ph.D. Molsoft L.L.C. San Diego, CA, USA Ruben Abagyan, Ph.D. Skaggs School of Pharmacy and Pharmaceutical Sciences University of California, San Diego La Jolla, CA, USA and San Diego Supercomputer Center University of California, San Diego La Jolla, CA, USA ISSN e-issn ISBN e-isbn DOI / Springer New York Dordrecht Heidelberg London Library of Congress Control Number: Springer Science+Business Media, LLC 2012 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. Printed on acid-free paper Humana Press is part of Springer Science+Business Media (

5 Preface Knowledge about protein tertiary structure can guide mutagenesis experiments, help in the understanding of structure function relationships, and aid the development of new therapeutics for diseases. Homology modeling is an in silico method that predicts the tertiary structure of a query amino acid sequence based on a homologous experimentally determined template structure. The method relies on the observation that the tertiary structure of a protein is better conserved than sequence and therefore two proteins that are not fully conserved at the sequence level may still share the same fold. Structures solved by X-ray crystallography and NMR are deposited in the Protein Data Bank (PDB) and form the templates for homology modeling. The human proteome has approximately 20,000 annotated human proteins and only 4,900 human protein fragments and domains can be found in the PDB. The main steps in a homology modeling experiment are template selection, alignment, backbone and side-chain prediction, and structure optimization, including ligand-guided optimization and evaluation. Errors at the template selection step will result in an incorrect model and so care is needed to identify a template structure that has significant homology with the query sequence. The template sequence is aligned to the query sequence and the alignment is adjusted to ensure optimal correspondence between the homologous regions. The backbone atoms of the model are mapped onto the three-dimensional template structure and nonconserved side-chain orientations are predicted. Optimization of the model in a force field removes steric clashes and improves the hydrogen-bonding network between atoms. Evaluation of the final model highlights regions where there are errors in the model, for example, nonconserved loops, which may need to be modeled independently of the conserved regions. While the ability of models to predict ligand binding is still limited as evaluated recently in a GPCR DOCK 2010 competition, there is noticeable progress. Energy sampling methods used in the homology modeling optimization step also have application for predicting how ligands bind to the model. Modeling methods are required even when an X-ray or NMR structure is available because the number of possible ligand receptor combinations is extremely high and experimentally solving all of them is not practical. In this book, experts in the field describe each homology modeling step from first principles, highlighting the pitfalls to avoid and providing first-hand solutions to common modeling problems. In addition, the book contains chapters from colleagues who model particularly challenging proteins such as membrane proteins where template structures are scarce or large macromolecular assemblies. The book also describes methods that can be applied once the initial model is complete, such as those which can be used to optimize the ligand-binding pocket of the model and predict protein protein interactions. We would like to express our sincere thanks to all the authors who so generously contributed their time and knowledge to this book. San Diego, CA, USA La Jolla, CA, USA Andrew J.W. Orry, Ph.D. Ruben Abagyan, Ph.D. v

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7 Contents Preface Contributors v ix 1 Classification of Proteins: Available Structural Space for Molecular Modeling Antonina Andreeva 2 Effective Techniques for Protein Structure Mining Stefan J. Suhrer, Markus Gruber, Markus Wiederstein, and Manfred J. Sippl 3 Methods for Sequence Structure Alignment Česlovas Venclovas 4 Force Fields for Homology Modeling Andrew J. Bordner 5 Automated Protein Structure Modeling with SWISS-MODEL Workspace and the Protein Model Portal Lorenza Bordoli and Torsten Schwede 6 A Practical Introduction to Molecular Dynamics Simulations: Applications to Homology Modeling Alessandra Nurisso, Antoine Daina, and Ross C. Walker 7 Methods for Accurate Homology Modeling by Global Optimization Keehyoung Joo, Jinwoo Lee, and Jooyoung Lee 8 Ligand-Guided Receptor Optimization Vsevolod Katritch, Manuel Rueda, and Ruben Abagyan 9 Loop Simulations Maxim Totrov 10 Methods of Protein Structure Comparison Irina Kufareva and Ruben Abagyan 11 Homology Modeling of Class A G Protein-Coupled Receptors Stefano Costanzi 12 Homology Modeling of Transporter Proteins (Carriers and Ion Channels) Aina Westrheim Ravna and Ingebrigt Sylte 13 Methods for the Homology Modeling of Antibody Variable Regions Aroop Sircar 14 Investigating Protein Variants Using Structural Calculation Techniques Jonas Carlsson and Bengt Persson vii

8 viii Contents 15 Macromolecular Assembly Structures by Comparative Modeling and Electron Microscopy Keren Lasker, Javier A. Velázquez-Muriel, Benjamin M. Webb, Zheng Yang, Thomas E. Ferrin, and Andrej Sali 16 Preparation and Refinement of Model Protein Ligand Complexes Andrew J.W. Orry and Ruben Abagyan 17 Modeling Peptide Protein Interactions Nir London, Barak Raveh, and Ora Schueler-Furman 18 Comparison of Common Homology Modeling Algorithms: Application of User-Defined Alignments Michael A. Dolan, James W. Noah, and Darrell Hurt Index

9 Contributors RUBEN ABAGYAN Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA ; San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA, USA ANTONINA ANDREEVA MRC Laboratory of Molecular Biology, Cambridge, UK ANDREW J. BORDNER Mayo Clinic, Scottsdale, AZ, USA LORENZA BORDOLI SIB Swiss Institute of Bioinformatics, Biozentrum University of Basel, Basel, Switzerland JONAS CARLSSON IFM Bioinformatics and SeRC (Swedish e-science Research Centre), Linköping University, Linköping, Sweden STEFANO COSTANZI Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA ANTOINE DAINA School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland MICHAEL A. DOLAN Bioinformatics and Computational Biosciences Branch, National Institute of Allergies and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA THOMAS E. FERRIN Resource for Biocomputing, Visualization, and Informatics, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA MARKUS GRUBER Center of Applied Molecular Engineering, Division of Bioinformatics, University of Salzburg, Salzburg, Austria DARRELL HURT Bioinformatics and Computational Biosciences Branch, National Institute of Allergies and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA KEEHYOUNG JOO Center for In Silico Protein Science, Center for Advanced Computation, Korea Institute for Advanced Study, Seoul, Korea VSEVOLOD KATRITCH Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA IRINA KUFAREVA Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA KEREN LASKER Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA ; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA ; California Institute for Quantitative Biosciences (QB3), University of California, San Francisco, San Francisco, CA, USA ; The Blavatnik School of Computer Science, Tel-Aviv University, Ramat Aviv, Israel ix

10 x Contributors JINWOO LEE Department of Mathematics, Kwangwoon University, Seoul, Korea JOOYOUNG LEE Center for In Silico Protein Science, Center for Advanced Computation, School of Computational Sciences, Korea Institute for Advanced Study, Seoul, Korea NIR LONDON Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Hadassah Medical School, The Hebrew University, Jerusalem, Israel JAMES W. NOAH Southern Research Institute, Birmingham, AL, USA ALESSANDRA NURISSO School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland ANDREW J.W. ORRY Molsoft L.L.C., San Diego, CA, USA BENGT PERSSON IFM Bioinformatics and SeRC (Swedish e-science Research Centre), Linköping University, Linköping, Sweden ; Science for Life Laboratory, Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden BARAK RAVEH Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Hadassah Medical School, The Hebrew University, Jerusalem, Israel ; The Blavatnik School of Computer Science, Tel-Aviv University, Ramat Aviv, Israel AINA WESTRHEIM RAVNA Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway MANUEL RUEDA Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA ; San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA, USA ANDREJ SALI Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA ; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA ; California Institute for Quantitative Biosciences (QB3), University of California, San Francisco, San Francisco, CA, USA ORA SCHUELER-FURMAN Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Hadassah Medical School, The Hebrew University, Jerusalem, Israel TORSTEN SCHWEDE SIB Swiss Institute of Bioinformatics, Biozentrum University of Basel, Basel, Switzerland MANFRED J. SIPPL Center of Applied Molecular Engineering, Division of Bioinformatics, University of Salzburg, Salzburg, Austria AROOP SIRCAR EMD Serono Research Center, Inc., Billerica, MA, USA STEFAN J. SUHRER Center of Applied Molecular Engineering, Division of Bioinformatics, University of Salzburg, Salzburg, Austria INGEBRIGT SYLTE Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway

11 Contributors xi MAXIM TOTROV Molsoft L.L.C., San Diego, CA, USA JAVIER A. VELÁZQUEZ-MURIEL Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA ; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA ; California Institute for Quantitative Biosciences (QB3), University of California, San Francisco, San Francisco, CA, USA ČESLOVAS VENCLOVAS Institute of Biotechnology, Vilnius University, Vilnius, Lithuania ROSS C. WALKER Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA ; San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA, USA BENJAMIN M. WEBB Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA ; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA ; California Institute for Quantitative Biosciences (QB3), University of California, San Francisco, San Francisco, CA, USA MARKUS WIEDERSTEIN Center of Applied Molecular Engineering, Division of Bioinformatics, University of Salzburg, Salzburg, Austria ZHENG YANG Resource for Biocomputing, Visualization, and Informatics, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA

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