Page i
Computational Molecular Biology
An Introduction
Page ii
WILEY SERIES IN MATHEMATICAL AND COMPUTATIONAL BIOLOGY
Editor-in-Chief
Simon Levin
Department of Ecology and Evolutionary Biology, Princeton University, USA
Associate Editors
Zvia Agur, Tel-Aviv University, Israel
Odo Diekmann, University of Utrecht, The Netherlands
Marcus Feldman, Stanford University, USA
Bryan Grenfell, Cambridge University, UK
Philip Maini, Oxford University, UK
Martin Nowak, Oxford University, UK
Karl Sigmund, University of Vienna, Austria
CHAPLAIN/SINGH/MCLACHLAN—On Growth and Form: Spatio-temporal Pattern Formation in Biology
CHRISTIANSEN—Population Genetics of Multiple Loci
CLOTE/BACKOFEN—Computational Molecular Biology: An Introduction
DIEKMANN/HEESTERBEEK—Mathematical Epidemiology of Infectious
Diseases: Model Building, Analysis and Interpretation
Reflecting the rapidly growing interest and research in the field of mathematical biology, this outstanding new book series
examines the integration of mathematical and computational methods into biological work. It also encourages the advancement
of theoretical and quantitative approaches to biology, and the development of biological organisation and function.
The scope of the series is broad, ranging from molecular structure and processes to the dynamics of ecosystems and the
biosphere, but unified through evolutionary and physical principles, and the interplay of processes across scales of biological
organisation.
Topics to be covered in the series include:
• Cell and molecular biology
• Functional morphology and physiology
• Neurobiology and higher function
• Immunology
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A fundamental research tool, the Wiley Series in Mathematical and Computational Biology provides essential and invaluable
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and epidemiology.
Page iii
Computational Molecular Biology
An Introduction
Peter Clote
Department of Computer Science and Department of Biology, Boston College, USA
Formerly
Ludwig-Maximilians-Universität München, Germany
Rolf Backofen
Ludwig-Maximilians-Universität München, Germany
Page iv
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Library of Congress Cataloging-in-Publication Data
Clote, Peter.
Computational biology : a self contained approach to bioinformatics
/ Peter Clote, Rolf Backofen
p. cm – (Wiley series in mathematical and computational biology)
Includes bibliographical references (p.)
ISBN 0-471-87251-2 (alk. paper) – ISBN 0-471-87252-0 (pbk.: alk. paper)
1. Genetics—Mathematical Models. 2. Molecular biology—
Mathematical models. I. Backofen, Rolf. II. Title. III. Series.
QH438.4.M3 C565 2000
572.8'01'51 187-dc21 00 -038169
British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British Library
ISBN 0-471-87251-2
ISBN 0-471-87252-0
Some content in the original version of this book is not available for inclusion in this electronic edition.
Produced from PostScript files supplied by the authors.
Printed and bound in Great Britain by Antony Rowe Ltd, Chippenham, Wiltshire.
This book is printed on acid-free paper responsibly manufactured from sustainable forestry
in which at least two trees are planted for each one used for paper production.
Page v
To my wife, Marie, and to my son, Nicolas. (P.C.)
To my wife, Doris, and my children, Ina and Lara. (R.B.)
Page vii
Contents
Series Preface xi
Preface xiii
1 1
Molecular Biology
1.1 Some Organic Chemistry 3
1.2 Small Molecules 4
1.3 Sugars 6
1.4 Nucleic Acids 6
1.4.1 Nucleotides 6
1.4.2 DNA 8
1.4.3 RNA 13
1.5 Proteins 14
1.5.1 Amino Acids 14
1.5.2 Protein Structure 15
1.6 From DNA to Proteins 17
1.6.1 Amino Acids and Proteins 17
1.6.2 Transcription and Translation 19
1.7 Exercises 21
Acknowledgements and References 22
2 23
Math Primer
2.1 Probability 23
2.1.1 Random Variables 25
2.1.2 Some Important Probability Distributions 27
2.1.3 Markov Chains 38
2.1.4 Metropolis–Hastings Algorithm 43
2.1.5 Markov Random Fields and Gibbs Sampler 47
2.1.6 Maximum Likelihood 52
2.2 Combinatorial Optimization 53
2.2.1 Lagrange Multipliers 53
2.2.2 Gradient Descent 54
2.2.3 Heuristics Related to Simulated Annealing 54
2.2.4 Applications of Monte Carlo 55
2.2.5 Genetic Algorithms 60
2.3 Entropy and Applications to Molecular Biology 61
2.3.1 Information Theoretic Entropy 62
2.3.2 Shannon Implies Boltzmann 63
Page viii
2.3.3 Simple Statistical Genomic Analysis 66
2.3.4 Genomic Segmentation Algorithm 69
2.4 Exercises 72
2.5 Appendix: Modification of Bezout's Lemma 77
Acknowledgements and References 79
3 81
Sequence Alignment
3.1 Motivating Example 83
3.2 Scoring Matrices 84
3.3 Global Pairwise Sequence Alignment 88
3.3.1 Distance Methods 88
3.3.2 Alignment with Tandem Duplication 99
3.3.3 Similarity Methods 110
3.4 Multiple Sequence Alignment 111
3.4.1 Dynamic Programming 112
3.4.2 Gibbs Sampler 112
3.4.3 Maximum-Weight Trace 114
3.4.4 Hidden Markov Models 117
3.4.5 Steiner Sequences 117
3.5 Genomic Rearrangements 118
3.6 Locating Cryptogenes and Guide RNA 120
3.6.1 Anchor and Periodicity Rules 122
3.6.2 Search for Cryptogenes 122
3.7 Expected Length of gRNA in Trypanosomes 123
3.8 Exercises 128
3.9 Appendix: Maximum-Likelihood Estimation for Pair Probabilities 132
Acknowledgements and References 133
4 135
All about Eve
4.1 Introduction 135
4.2 Rate of Evolutionary Change 137
4.2.1 Amino Acid Sequences 137
4.2.2 Nucleotide Sequences 139
4.3 Clustering Methods 144
4.3.1 Ultrametric Trees 147
4.3.2 Additive Metric 152
4.3.3 Estimating Branch Lengths 156
4.4 Maximum Likelihood 157
4.4 1 Likelihood of a Tree 159
4.4.2 Recursive Definition for the Likelihood 160
4.4.3 Optimal Branch Lengths for Fixed Topology 162
4.4.4 Determining the Topology 166
4.5 Quartet Puzzling 166
4.5.1 Quartet Puzzling Step 169
4.5.2 Majority Consensus Tree 170
4.6 Exercises 171
Page ix
Acknowledgements and References 173
5 175
Hidden Markov Models
5.1 Likelihood and Scoring a Model 177
5.2 Re-estimation of Parameters 180
5.2.1 Baum–Welch Method 181
5.2.2 EM and Justification of the Baum–Welch Method 184
5.2.3 Baldi–Chauvin Gradient Descent 187
5.2.4 Mamitsuka's MA Algorithm 191
5.3 Applications 193
5.3.1 Multiple Sequence Alignment 193
5.3.2 Protein Motifs 194
5.3.3 Eukaryotic DNA Promotor Regions 195
5.4 Exercises 197
Acknowledgements and References 198
6 201
Structure Prediction
6.1 RNA Secondary Structure 202
6.2 DNA Strand Separation 213
6.3 Amino Acid Pair Potentials 223
6.4 Lattice Models of Proteins 228
6.4.1 Monte Carlo and the Heteropolymer Protein Model 231
6.4.2 Genetic Algorithm for Folding in the HP Model 233
6.5 Hart and Istrial's Approximation Algorithm 234
6.5.1 Performance 234
6.5.2 Lower Bound 236
6.5.3 Block Structure, Folding Point, and Balanced Cut 239
6.6 Constraint-Based Structure Prediction 243
6.7 Protein Threading 246
6.7.1 Definition 246
6.7.2 A Branch-and-Bound Algorithm 249
6.7.3 NP-hardness 258
6.8 Exercises 259
Acknowledgements and References 261
Appendix A 263
Mathematical Background
A.1 Asymptotic complexity 263
A.2 Units of Measurement 263
A.3 Lagrange Multipliers 264
Appendix B 265
Resources
B.1 Web Sites 265
B.2 The PDB Format 266
References 269
Index 281
Page 281
Index
absolute performance 236
addition law 24
additive metric 152
additive tree metric 147
additivity of alignments 90, 95
adenine 8
adenoside triphosphate (ATP) 4–6
alcohol 5
alignment 88, 90–5, 97–110
additivity 90, 95
distance 88, 90, 100
alleles 11–12
amine 5
amino acids 6, 14–15, 17–19
codes 18
pair potentials 35, 223–8
pair probabilities 86–8
sequences 137–9
substitution matrix methods 139
amino group 4, 5, 14
aminoacyl-tRNA synthetase 20, 21
Amoeba dubia 12
anchor region rules 122
antiparallel ß sheets 16
Archaea 1
archaebacteria 1
asymptotic complexity 263
asymptotic performance 236
Australopithecus 135
Avogadro's number 38
B
back mutations 137, 138
backtrack 210
balanced cut 239–42
balanced state 44
Baldi–Chauvin gradient descent 187–91
Bernouilli random variable 27, 28
Baldi-Chauvin updates 188–91
bases, chemical forms 8
basic U-folds 239
Baum–Welch method 180–8
Baum–Welch parameter 184
Baum–Welch score 178, 179
Bayes' rule 25
Bender's theorem 205
Bernouilli trial 27
ß sheet 16
Bezout's Lemma 77–9
binary phylogenetic trees 145–7
binary trees 144, 145, 166
binomial coefficients 24
binomial distribution 27–8
bioinformatics 2
block-respecting codes 56, 57, 59
block structure 239–42
block-structured code 56
BLOSUM matrices 88
Boltzmann distribution 35–8, 45, 46, 181, 221
Boltzmann probability 45, 46
Boltzmann probability distribution 63, 64
Boltzmann's constant 38, 66
Boltzmann's law 63
boolean cellular automation 74
Box–Muller algorithm 32
branch-and-bound algorithm 249–58
branch lengths 156–7, 162–5
Brookhaven Protein Database (PDB) 266
C
Cantor–Bendixson derivative 207
carbohydrates 4
carboxyl group 4, 5, 14
carboxylic acid 5
Page 282
catalan numbers 204
CATH database 266
Cavalli-Sforza–Edwards theorem 145–7
central limit theorem 31
chaperones 21
chloroplast DNA (cpDNA) 140
chromosomal duplication 119
chromosomal rearrangement 119
chromosomes 9, 12, 60, 119, 233–4
clustering methods 144–57
codons 17
combinatorial optimization 53–61
exercises 73–5
complete maximum-weight trace (CMWT) formalization 114
computational biology 2
conditional likelihood 161–2
conditional probability 25, 49–50, 181
connected neighbors 229
constraint-based structure prediction 243–6
core model 247–8, 259
covalent bond 3
Cro Magnon 135–6
crossover 61
cryptogenes 120–3
cyanobacteria 1 cytosine 8
cytosine 8
Dempster et al. theorem 186
deoxyribose 7
dinucleotide entropy 67–8
directed graph 144
discrete Markov model 175
distance matrix 94, 154
disulfide bonds 17
divergence 67
DNA 2, 8–12
DNA replication 21
DNA strand separation 213–23
Drosophilia 197
duplication 119
dynamic programming 112
dynamic programming algorithm 107
edit distance 88–90
edit operation 89
energy functions 213
energy matrix computation 210
enthalpy 66
entropy 61–72
exercises 75–6
information theoretic 62–3
equilibrium distribution 42, 45, 46
ergodic state 44
error distance 192
Escherichia coli 1
ester 5
Eukarya 2
eukaryotes 1, 20
eukaryotic DNA 214
promotor regions 195–7
promotor sequence 196
evolution rates 135–74
change rate 137–44
exercises 171–3
expectation maximization 180
expectation maximization algorithm 184–7
expected number of transitions 180, 182
exponential distribution 30, 33–4
extrachromosomal element (ECE) 9
Farris transformed distance method 154
fatty acids 4
Feller theorem 34
fibrinopeptides 140
fission 119
Fitch–Margoliash method 156–7
foldicity 231
folding 233–4
hydrophobic force 235
folding point 239–42
forward method 178
forward variable, definition 178–9
fusion 119
gap function 111
gap penalty 94–5, 111
Gaussian distribution 30
Geman–Geman theorem 51
gene 11
GENEMARK 47
genetic algorithms 60–1, 233–4
Page 283
genetic code 18, 19
fault tolerant 55–60
optimality 55–60
genome 11
genomic analysis 66–8
genomic rearrangements 118–20
genomic segmentation algorithm 69–72
genomic signature 68
geometric distribution 28–9
Gibbs distribution 47–9, 51
Gibbs free energy 38
Gibbs sampler 47–52, 112
global pairwise sequence alignment 88–111
Gotoh algorithm 82, 100–2
Gotoh theorem 96
gradient descent method 54, 180
GU base pairs 205, 209
guanine 8
guide RNA (gRNA) 13, 20, 120–3, 123–8
Haemophilus influenzae 67, 68
Hamming distance 205
Hart–Istrail approximation algorithm 234–42
heteropolymer protein model 231
hidden Markov models (HMM) 117, 175–99
applications 193–7
exercises 197–8
urn model 176
Homo erectus 135
Homo habilis 135
homologous modeling 201
homologous proteins 83–4
homology testing 81
hydrocarbon molecule 4
hydrogen bonds 3, 9, 17
hydrophilic amino acid 229
hydrophilic molecules 3
hydrophobic amino acid 229
hydrophobic force 4, 17
hydrophobic molecules 4
hydroxyl group 4, 5
hypergeometric distribution 32
information (entropy) 62
information flow 2
information theoretic entropy 62–3
interaction graph 248–9
inter-chromosomal events 119
internal energy 66
intra-chromosomal events 119
inversion 119
Jaccard's index 76
Jensen-Shannon divergence 69–70
Kececioglu, Li, Tromp algorithm 118
Kececioglu theorem 116
Kronecker δ-function 144, 158
L. tarenolae 121
Lagrange multipliers 53–4, 59, 63, 64, 132, 219, 264
lattice connectivity constant 236
lattice models of proteins 228–34
Lawrence, Altschul, Boguski, Liu, Neuwald, Wootton algorithm 113
least common ancestor 154
likelihood 177–80
recursive definition 160–2
linking number 214
local alignments 111
local move set 231–2
log odds ratios 86
majority consensus tree 170–1
Mamitsuka's MA algorithm 191–3
Mamitsuko's updates 192–3
Markov chain 38–43, 127, 140, 141, 220
definition 176
irreducible 39
reversible 42
stationary 39, 42
Markov chain Monte Carlo algorithm 43
Markov matrix 141
Markov model 125
definition 177
order 176
Markov process 140
Markov property 140–1, 176
Markov random fields 47–51
mathematical concepts 23–79
mathematical models 23
maximal entropy probability distribution 65
Page 284
maximum entropy 66
maximum likelihood estimation 52–3, 117, 157–66, 184
maximum-likelihood estimation, pair probabilities 132–3
maximum-weight trace 114–17
mean square difference 56
meiosis 12, 21
messenger RNA (mRNA) 13, 20, 120
Methanococcus jannaschii 1, 2, 9, 67–70, 266
methionine 21
metric 147
definition 90
Metropolis et al. theorem 46
Metropolis–Hastings algorithm 35, 37, 43–7
mitochondrial DNA (mtDNA) 136, 140
mitosis 12, 21
molecular biology
exercises 21–2
overview 1–22
molecular fossils 13
molecular fossils 13
Monte Carlo algorithm 43, 220
Monte Carlo applications 55–60
Moore automation 125, 127
motifs 16
multiloops 207
multinomial coefficients 24
multinomial distribution 28
multiple sequence alignment 111–18, 193
multiregional model 135
multivariate function 186–7
mutations 137, 138
Mycoplasma genitalia 68
Needleman–Wunsch algorithm 107
Needleman–Wunsch edit distance 91–4
neighbor relation 166
neighborhood system 44
net pairwise potential 225
neutral networks 203, 205
neutral substitutions 139
non-covalent bond 3
normal distribution 30–1
normalized specific amino acid distance frequency 225
NP-hardness 258
nuclear magnetic resonance (NMR) studies 226
nucleic acids 6–13
nucleotide entropy 66–8
nucleotide sequences 66, 139–44
nucleotides 4–8
forms 8
Nussinov–Jacobson matrix 208
odds ratio 86
oligonucleotides 6
open reading frame (ORF) 12
operational taxonomic unit (OTU) 137
ordering constraints 248
organic chemistry 3
overlay matrices 100
pair group method (PGM) 148
pair probabilities, maximum-likelihood estimation 132–3
PAM matrices 86–8, 139, 140
parallel ß sheets 16
parallel mutations 137, 138
partition function 43, 48, 65
PDB format 266
peptide bond 14
percent minimization 59
performance, definition 234–6
periodicity rules 122
persistence, definition 39
phosphodiester bond 8
phylogenetic trees 136, 145, 148
pivot moves 232
Poisson distribution 29–30, 34
Poisson process 138
polar requirement 17
polarity index 58
polymer, definition 4
polysaccharides 4
positive transition matrix 42
potential energy function 48
primary structure 17, 202
principle of insufficient reason 63
probability density function 25
probability distributions 27–38
probability function 24
Page 285
probability theory 23–53
exercises 72–3
prokaryotes 1, 19, 20
protein 2
protein data bank (PDB) 266
protein folding problem 201 see also folding
protein motifs 194–5
protein structure 15–17
prediction 201–62
protein threading 202, 246–59
definition 246–9
proteins 14–19
Protokarya 2
Pulley Principle 162
purines 8
pyramidines 8
quarternary structure 17
quartet puzzling step 166–70
quartet trees 166–8
Ramachandran plot 15
random boolean cellular automation 74
random sequence 118
random variables 25–6, 31
reciprocal translocation 119
record-to-record Travel algorithm (RRT) 55
recursion equation 92, 95, 104–7
re-estimation of parameters 180
reference amino acid distance frequency 224
relative threading 253
restriction enzymes 81–2
reverse transcriptases 83–4
reversible Markov process 158
ribose 7
ribosomal RNA (rRNA) 13, 21
ribosomes 21
RNA 2, 13
RNA polymerase 19, 195
RNA secondary structure 202–13
root mean square deviation (RMSD) 156
roulette wheel technique 61
Saccharomyces cerevisiae 266
saddlepoint 52
salt bridges 17
SCOP database 266
scoring a model 177–80
scoring function 249, 259
scoring matrices 84–6
scoring subsequence 111
secondary structure 17, 202
elements 16
segment algorithm 71
segmentation algorithm 32
selenocysteine 56
sequence alignment 81–134
example 83–4
exercises 128–32
sequence space 205
Shannon entropy function 64
Shannon's formula 62
shape space 205
shuffle algorithm 61
shuffled-codon codes 56, 58
similarity methods 110–11
simulated annealing 43–4, 46, 220
heuristics related to 54–5
Sinclair theorem 43
single-molecule DNA sequencing 117
small molecules 4–6
small nuclear (snRNA) 13
Smith–Waterman local sequence alignment 120
spacing constraints 248
specific amino acid distance frequencies 225
standard deviation 26
standard error 31
statistical model 175
statistical significance 69
StatSignificance algorithm 71
Steiner sequences 117–18
Stirling's approximation 146
Stirling's formula 24–5, 62
stochastic matrix 38
Strimmer, von Haeseler algorithm 168
structure prediction 201–62
constraint-based 243–6
exercises 259–62
sugar molecule 4
sugar transport proteins 195
sugars 6
Page 286
sum-of-pairs multiple sequence alignment problem 114
supercoiled DNA 218, 220
supersecondary structures 16
SWISS-PROT 266
synonymous substitutions 139
syntenic distance 119, 120
synteny 119
tandem duplication 99–110
TATA box 12, 19, 195–6
taxon 137
Taylor expansion 29, 143
tertiary structure 17, 201, 202
thermal luminescence 135
threading sets 253
threshold accepting (TA) algorithm 54–5
thymine 8
topological neighbors 229
total free energy 220
total probability formula 25
trace matrix 93, 98
traceback 93, 94, 98, 107, 179, 180
transcription 19–21
transfer RNA (tRNA) 13, 20–1
transition probability functions 141
transitional mutations 140
transitions 110, 127–8
translation 19–21
transposition 119
transversion 110
transversional mutations 140
tree 145
likelihood 159–60
topology 166
Trypanosoma brucei 1
trypanosomes 123–8
ultrametric trees 147–52
Unger–Moult hybrid genetic algorithm 233
unit evolutionary time 138
units of measurement 263–4
UPGMA 148–9, 152, 154–5, 157
uracil 8
variance 26
Viterbi algorithm 180
Viterbi score of a model 179
WAC matrix 139
water molecule 4
Waterman, Smith and Beyer theorem 95–6
Watson–Crick base pairs 121, 124, 205, 209
Watson–Crick model 8
Watson–Crick rules 8
web sites 266
WPGMA 151, 156
Wraparound Dynamic Programming 107, 108
wraparound step 101, 102
