An Introduction to Computational Biochemistry

370 Pages·2002·6.274 MB·English

by  C. Stan Tsai

AN INTRODUCTION TO
COMPUTATIONAL
BIOCHEMISTRY
AN INTRODUCTION TO
COMPUTATIONAL
BIOCHEMISTRY
C. Stan Tsai, Ph.D.
Department of Chemistry
and Institute of Biochemistry
Carleton University
Ottawa, Ontario, Canada
A JOHN WILEY & SONS, INC., PUBLICATION
a
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Tsai,C.Stan.
Anintroductiontocomputationalbiochemistry/C.StanTsai.
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Includesbibliographicalreferencesandindex.
ISBN0-471-40120-X(pbk.:alk.paper)
1.Biochemistry--Dataprocessing.2.Biochemistry--Computersimulation.3.
Biochemistry--Mathematics.I.Title.
QP517.M3T7332002
572(cid:1).0285--dc21 2001057366
PrintedintheUnitedStatesofAmerica.
10 9 8 7 6 5 4 3 2 1
CONTENTS
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
1
INTRODUCTION 1
1.1. Biochemistry: Studies of Life at the Molecular Level . . . . . . . . . 1
1.2. Computer Science and Computational Sciences . . . . . . . . . . . . . 5
1.3. Computational Biochemistry: Application of Computer
Technology to Biochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2
BIOCHEMICAL DATA: ANALYSIS AND
MANAGEMENT 11
2.1. Statistical Analysis of Biochemical Data . . . . . . . . . . . . . . . . . . 11
2.2. Biochemical Data Analysis with Spreadsheet Application . . . . . 20
2.3. Biochemical Data Management with Database Program . . . . . . 28
2.4. Workshops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3
BIOCHEMICAL EXPLORATION: INTERNET RESOURCES 41
3.1. Introduction to Internet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3.2. Internet Resources of Biochemical Interest . . . . . . . . . . . . . . . . . 46
3.3. Database Retrieval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
3.4. Workshops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
4
MOLECULAR GRAPHICS: VISUALIZATION OF
BIOMOLECULES 53
4.1. Introduction to Computer Graphics . . . . . . . . . . . . . . . . . . . . . 53
4.2. Representationof Molecular Structures . . . . . . . . . . . . . . . . . . . 56
4.3. Drawing and Display of Molecular Structures . . . . . . . . . . . . . . 60
4.4. Workshops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 v
vi CONTENTS
5
BIOCHEMICAL COMPOUNDS: STRUCTURE AND
ANALYSIS 73
5.1. Survey of Biomolecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
5.2. Characterization of Biomolecular Structures . . . . . . . . . . . . . . . 80
5.3. Fitting and Search of Biomolecular Data and Information . . . . 87
5.4. Workshops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
6
DYNAMIC BIOCHEMISTRY: BIOMOLECULAR
INTERACTIONS 107
6.1. Biomacromolecule—Ligand Interactions . . . . . . . . . . . . . . . . . . . 107
6.2. Receptor Biochemistry and Signal Transduction . . . . . . . . . . . . 111
6.3. Fitting of Binding Data and Search for Receptor Databases . . . 113
6.4. Workshops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
7
DYNAMIC BIOCHEMISTRY: ENZYME KINETICS 123
7.1. Characterization of Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
7.2. Kinetics of Enzymatic Reactions . . . . . . . . . . . . . . . . . . . . . . . . 126
7.3. Search and Analysis of Enzyme Data . . . . . . . . . . . . . . . . . . . . . 133
7.4. Workshops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
8
DYNAMIC BIOCHEMISTRY: METABOLIC SIMULATION 147
8.1. Introduction to Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
8.2. Metabolic Control Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
8.3. Metabolic Databases and Simulation . . . . . . . . . . . . . . . . . . . . . 153
8.4. Workshops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
9
GENOMICS: NUCLEOTIDE SEQUENCES AND
RECOMBINANT DNA 165
9.1. Genome, DNA Sequence, and Transmission of Genetic
Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
9.2. Recombinant DNA Technology . . . . . . . . . . . . . . . . . . . . . . . . . 169
9.3. Nucleotide Sequence Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . 171
9.4. Workshops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
CONTENTS vii
10
GENOMICS: GENE IDENTIFICATION 183
10.1. Genome Information and Features . . . . . . . . . . . . . . . . . . . . . 183
10.2. Approaches to Gene Identification . . . . . . . . . . . . . . . . . . . . . . 185
10.3. Gene Identification with Internet Resources . . . . . . . . . . . . . . . 188
10.4. Workshops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
11
PROTEOMICS: PROTEIN SEQUENCE ANALYSIS 209
11.1. Protein Sequence: Information and Features . . . . . . . . . . . . . . 209
11.2. Database Search and Sequence Alignment . . . . . . . . . . . . . . . . 213
11.3. Proteomic Analysis Using Internet Resources:
Sequence and Alignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
11.4. Workshops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
12
PROTEOMICS: PREDICTION OF PROTEIN STRUCTURES 233
12.1. Prediction of Protein Secondary Structures from Sequences . . 233
12.2. Protein Folding Problems and Functional Sites . . . . . . . . . . . . 236
12.3. Proteomic Analysis Using Internet Resources: Structure
and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
12.4. Workshops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
13
PHYLOGENETIC ANALYSIS 269
13.1. Elements of Phylogeny . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
13.2. Methods of Phylogenetic Analysis . . . . . . . . . . . . . . . . . . . . . . 271
13.3. Application of Sequence Analyses in Phylogenetic Inference . . 275
13.4. Workshops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
14
MOLECULAR MODELING: MOLECULAR MECHANICS 285
14.1. Introduction to Molecular Modeling . . . . . . . . . . . . . . . . . . . . 285
14.2. Energy Minimization,Dynamics Simulation, and
Conformational Search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
14.3. Computational Application of Molecular Modeling Packages . 296
14.4. Workshops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
15
MOLECULAR MODELING: PROTEIN MODELING 315
15.1. Structure Similarity and Overlap . . . . . . . . . . . . . . . . . . . . . . . 315
15.2. Structure Prediction and Molecular Docking . . . . . . . . . . . . . . 319
viii CONTENTS
15.3. Applications of Protein Modeling . . . . . . . . . . . . . . . . . . . . . . 322
15.4. Workshops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
APPENDIX 343
1. List of Software Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
2. List of World Wide Web Servers . . . . . . . . . . . . . . . . . . . . . . . . . 345
3. Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
INDEX 357
PREFACE
Since the arrival of information technology, biochemistry has evolved from an
interdisciplinary role to becoming a core program for a new generation of interdis-
ciplinarycoursessuchasbioinformaticsandcomputationalbiochemistry.Ademand
exists for an introductory text presenting a unified approach for the combined
subjects that meets the need of undergraduate science and biomedical students.
Thistextbookis theintroductorycoursewareat anentryleveltoteachstudents
biochemical principles as well as the skill of using application programs for
acquisition, analysis, and management of biochemical data with microcomputers.
Thebookiswrittenforendusers,notforprogrammers.Theobjectiveistoraisethe
students’ awareness of the applicability of microcomputers in biochemistry and to
increasetheir interest in the subject matter. The target audiencesare undergraduate
chemistry, biochemistry, biomedical sciences, molecular biology, and biotechnology
students or new graduate students of the above-mentioned fields.
Every field of computational sciences including computational biochemistry is
evolving at such a rate that any book can seem obsolete if it has to discuss the
technology. For this reason, this text focuses on a conceptual and introductory
description of computational biochemistry. The book is neither a collection of
presentationsofimportantcomputationalsoftwarepackagesinbiochemistrynorthe
exaltation of some specific programs described in more detail than others. The
author has focused on the description of specific software programs that have been
used in his classroom. This does not mean that these programs are superior to
others.Rather,this text merely attemptsto introducetheundergraduatestudents in
biochemistry, molecular biology, biotechnology, or chemistry to the realm of
computer methods in biochemical teaching and research. The methods are not
alternatives to the current methodologies, but are complementary.
This text is not intended as a technical handbook. In an area where the speed
of change and growth is unusually high, a book in print cannot be either compre-
hensive or entirely current. This book is conceived as a textbook for students who
havetakenbiochemistryandarefamiliarwiththegeneraltopics.However,thebook
aims to reinforce subject matter by first reviewing the fundamental concepts of
biochemistrybriefly.Thesearefollowedby overviewson computationalapproaches
to solve biochemical problems of general and special topics.
Thisbookdelvesintopracticalsolutionstobiochemicalproblemswithsoftware
programs and interactive bioinformatics found on the World Wide Web. After the
introductioninChapter1,theconceptofbiochemicaldataanalysisandmanagement
is described in Chapter 2. The interactions between biochemists and computers are
ix
x PREFACE
the topics of Chapter 3 (Internet resources) and Chapter 4 (computer graphics).
Computational applications in structural biochemistry are described in Chapter 5
(biochemical compounds) and then in Chapters 14 and 15 (molecular modeling).
Dynamic biochemistry is treated in Chapter 6 (biomolecular interactions), Chapter
7(enzymekinetics),andChapter8(metabolicsimulation).Informationbiochemistry
that overlaps bioinformatics and utilizes the Internet resources extensively is dis-
cussed in Chapters 9 and 10 (genomics), Chapters 11 and 12 (proteomics), and
Chapter 13 (phylogenetic analysis).
Iwouldliketothankalltheauthorswhoelucidatesequencesand3Dstructures
of nucleic acidsas wellas proteins,and theykindly placesuchvaluable information
in the public domain. The contributions of all the authors who develop algorithms
for free access on the Web sites and who provide highly useful software programs
for free distribution are gratefully acknowledged. I thank them for granting me the
permissions to reproduce their web pages, online and e-mail returns. I am grateful
to Drs. Athel Cornish-Bowden (Leonora), Tom Hall (BioEdit), Petr Kuzmic
(DynaFit), and Pedro Mendes (Gepasi) for the consents to use their software
programs. The effort of all the developers and managers of the many outstanding
Web sites are most appreciated. The development of this text would not have been
possiblewithoutthecontributionandgenerosityof theseinvestigators,authors,and
developers.Iam thankful toDr. D. R. Wilesforreading parts of this manuscript.It
ismy pleasuretostatethatthewritingof this texthasbeenafamily effort.Mywife,
Alice, has been most instrumental in helping me complete this text by introducing
and continuouslycoachingme on the wonderful world of microcomputers.My son,
Willis, and my daughter, Ellie, have assisted me in various stages of this endeavor.
The credit for the realization of this textbook goes to Luna Han, Editor, and
DanielleLacourciere,AssociateManagingEditor,ofJohnWiley&Sons.Thisbook
is dedicated to Alice.
C. Stan Tsai
Ottawa,Ontario,Canada
AnIntroductiontoComputationalBiochemistry.C.StanTsai
Copyright(cid:182)2002byWiley-Liss,Inc.
ISBN:0-471-40120-X
1
INTRODUCTION
Theuseofmicrocomputerswillcertainlybecomeanintegralpartofthebiochemistry
curriculum. Computational biochemistry is the new interdisciplinary subject that
applies computer technology to solve biochemical problems and to manage and
analyze biochemical information.
1.1. BIOCHEMISTRY: STUDIES OF LIFE AT THE MOLECULAR LEVEL
All the living organisms share many common attributes, such as the capability to
extract energy from nutrients, the power to respond to changes in their environ-
ments,andtheabilitytogrow,todifferentiate,andtoreproduce.Biochemistryisthe
study of life at the molecular level (Garrett and Grisham, 1999; Mathews and van
Holde, 1996; Voet and Voet, 1995; Stryer, 1995; Zubay, 1998). It investigates the
phenomena of life by using physical and chemical methods dealing with (a) the
structuresofbiologicalcompounds(biomolecules),(b)biomoleculartransformations
and functions, (c) changes accompanying these transformations, (d) their control
mechanisms, and (e) impacts arising from these activities.
The distinct feature of biochemistry is that it uses the principles and language
ofonescience,chemistry,toexplaintheotherscience,biologyatthemolecularlevel.
Biochemistry can be divided into three principal areas: (1) Structural biochemistry
focuses on the structural chemistry of the components of living matter and the
relationship between chemical structure and biological function. (2) Dynamic bio-
chemistrydealswiththetotalityofchemicalreactionsknownasmetabolicprocesses
that occur in living systems and their regulations. (3) Information biochemistry is
1