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COMPUTER-ASSISTED MODELING Contributions of Computational Approaches to Elucidating Macromolecular Structure and Function Committee on Computer-Assisted Modeling Board on Basic Biology Commission on Life Sciences National Research Council National Academy Press Washington, D.C. 1987
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NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competence and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Frank Press is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Robert M. White is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Samuel O. Thier is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Frank Press and Dr. Robert M. White are chairman and vice chairman, respectively, of the National Research Council. This study by the Board on Basic Biology was conducted under Contract No. D~FGO1- 86ER60457 with the U.S. Department of Energy. Copies of this report can be obtained from the National Academy Press, 2101 Consti- tution Avenue, N.W., Washington, DC 20418, for S3.00 per copy prepaid. Supplies are limited. Printed in the United States of America Cover: Connolly-Richards Solvent-accessible surfaces of trypsin, thymidylate synthase and carbonic anhydrase. Coordinates from the Protein Data Bank, Brookhaven National Laboratory, and R. Stroud, University of California/San Francisco. Photographs taken by R. Desjarlais and B. Shoichet, University of California/San Francisco, using the facilities of the Computer Graphics Laboratory.
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COMMlTTl:E ON CO=?UTER-ASSISTED MODELING IRWIN D. KUNTZ (Chairman), University of California, San Francisco DAVID R. DAVIES, National Institutes of Health, Bethesda, Maryland RICHARD E. DICKERSON, University of California, Los Angeles RUSSELL F. DOOLITTLE, University of California, San Diego RICHARD J. FELDMANN, National Institutes of Health, Bethesda, Maryland JAN HERMANS, University of North Carolina, Chapel Hill YVONNE C. MARTIN, Abbott Laboratories, Abbott Park, Illinois JAMES H. PRESTEGARD, Yale University, New Haven, Connecticut PETER J. ROSSKY, University of Texas, Austin HAROLD A. SCHERAGA, CorneD University, Ithaca, New York DENNIS H. SMITH, Molecular Design [td., San I,eandro, California CHARLES C. SWEELEY, Michigan State University, East I~ans~ng IGNAClO TINOCO, University of California, Berkeley WAI,TER G. ROSEN, Senior PTO9Tam OfflCeT SUSAN WALTON, Editor LINDA MILLER POORE, senior secretary ·.- 111
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BOARD ON BASIC BIOLOGY FRANCISCO J. AYALA (Chairman), University of California, Davis NINA V. FEDOROFF, Carnegie Institution of Washington, Baltimore, Maryland TIMOTHY H. GOLDSMITH, Yale University, New Haven, Connecticut RALPH W. F. HARDY, CorneD University, Ithaca, New York ERNEST G. JAWORSKI, Monsanto Company, St. Louis, Missouri SIMON A. LEVIN, Cornell University, Ithaca, New York HAROLD A. MOONEY, Stanford University, Stanford, California HAROI,D J. MOROWITZ, Yale University, New Haven, Connecticut WILLIAM E. PAUL, National Institutes of Health, Bethesda, Maryland DAVID D. SABATINI, New York University, New York City MALCOLM S. STEINBERG, Princeton University, Princeton, New Jersey JOSEPH E. VARNER, Washington University, St. I,ouis, Missouri DAVID B. WAKE, University of California, Berkeley JOHN E. DOWI.ING (ex-o~cio), Harvard University, Cambridge, Massachusetts JOHN E. BURRIS, Director 1V
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COMMISSION ON LIFE SCIENCES JOHN E. DOWLING (Chairman), Harvard University, Cambridge, Massachusetts PERRY I,. ADKISSON, The lexas A&M University System, College Station FRANCISCO J. AYALA, University of California, Davis J. MICHAEL BISHOP, The G.W. Hooper Research Foundation, San Erancisco, California NINA V. FEDOROFF, Carnegie Institution of Washington, Baltimore, Maryland TIMOTHY H. GOLDSMITH, Yale University, New Haven, Connecticut RICHARD W. HANSON, Case Western Reserve University School of Medicine, Cleveland, Ohio RALPH W. F. HARDY, CorneD University, Ithaca, New York RICHARD ]. HAVEL, University of California, San Francisco, School of Medicine DONALD F. HORNIG, Harvard School of Public Health, Boston, Massachusetts ERNEST G. JAWORSKI, Monsanto Company, St. Louis, Missouri SIMON A. LEVIN, Cornell University, Ithaca, New York FRANKLIN M. LOEW, School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts ROBERT W. MANN, Massachusetts Institute of Technology, Cambridge, Massachusetts HAROLD A. MOONEY, Stanford University, Stanford, California JOSEPH E. RALL, National Institutes of Health, Bethesda' Maryland RICHARD D. REMINGTON, University of Iowa, Iowa City RICHARD B. SETLOW, Brookhaven National Laboratory, Upton, New York JOSEPH E. VARNER, Washington University, St. Louis, Missouri ALVIN G. LAZEN, Executive Director v
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Preface The committee, asked to provide an assessment of computer- assisted modeling of molecular structure, has highlighted the signal successes and the significant limitations for a broad panoply of technologies and has projected plausible paths of development over the next decade. As with any assessment of such scope, differing opinions about present or future prospects were expressed. The conclusions and recommendations, however, represent a consensus of our views of the present status of computational efforts in this field. The committee's task was made easier by colleagues who gen- erously provided us with the benefit of their expertise. We wish particularly to thank Peter GooUford, William Jorgensen, and Andrew McCammon. The committee is indebted to the excellent National Research Council staff whose work greatly expedited the production of this report. Special thanks are due to Linda Poore, Susan Walton, and, particularly, to Walter Rosen for unfailing help and guidance. Irwin D. Kuntz Chairman · - V11
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Contents 1. Executive Summary . . e e e e e e ~ e e e e ~ e ~ e e e ~ e ~ e e e e ~ e e e e e e e e ~ ~ e e ~ ~ e 1 2e Introduction eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee~eee~ 18 Be Primary Structure of Proteins and Nucleic Acids . eeeee~ 23 Protein Sequences and Data Bases, 23 Pattern Based Comparisons, 28 4e Secondary Structure of Proteins and Nucleic Acids Proteins, 32 Nucleic Acids, 36 Se Tertiary Structure of Proteins and Nucleic Acids: Experimental e e ~ ~ e e e e e e e e e e e e e e e e ~ ~ ~ e e e ~e e e e X-Ray Diffraction of Biological Macromolecules, 41 Computer-Assisted Modeling in DNA Structure Analysis, 44 Using Nuclear Magnetic Resonance to Determine Tertiary Structures, 57 Areas of Potential Impact of NMR, 62 Demand on Computational Facilities, 66 6. Tertiary Structure of Proteins and Nucleic Acids: e e ~3 2 .41 Theory . eeeeeeeeeee~eee ~eeeeee ~en 69 Energy Optimization, 69 Molecular Dynamics, 77 Results, 79 1X
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Salvation and Electrostatics in Computer Simulation of Biopolymers, 88 Heuristic Methods, 99 Hierarchical Models of Protein Folding, 102 Pattern Recognition and Artificial Intelligence, 103 7. Functional Aspects of Proteins and Nucleic Acids .. Catalysis, 106 Designing New Protein Structures, 108 Predicting Function from a Predicted Three-Dimensional Structure, 114 8. Structure and Function of Complex Carbohydrates Biological Function, 131 Biosynthesis of N- Linked Glycoproteins and Glycosphingolipids, 133 Analysis of Primary and Tertiary Structure, 137 X-Ray Analysis of Crystal Structures of Carbohydrates, 138 NMR Solution Structures of Carbohydrates, 140 ...... 106 ...... 131 Suprarnolecular Structure, 142 9. Hardware ~ eeeeeeeeee ~144 Central versus Distributed Computing, 149 Computer Utilization in the next 5 to 10 Years, 149 The National Supercomputer Network, 150 Local Area Networks, 151 Data Base Use, 151 Competitiveness, 152 10. Conclusions and Recommendations 154 References Conclusions, 154 Recommendations, 157 x .160