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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
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