Table of Contents
Preface of the First Edition xv
Preface of the Second Edition xvii
1 Networks in Biological Cells 1
1.1 Some Basics About Networks 1
1.1.1 Random Networks 2
1.1.2 Small-World Phenomenon 2
1.1.3 Scale-Free Networks 3
1.2 Biological Background 4
1.2.1 Transcriptional Regulation 5
1.2.2 Cellular Components 5
1.2.3 Spatial Organization of Eukaryotic Cells into Compartments 7
1.2.4 Considered Organisms 8
1.3 Cellular Pathways 8
1.3.1 Biochemical Pathways 8
1.3.2 Enzymatic Reactions 11
1.3.3 Signal Transduction 11
1.3.4 Cell Cycle 12
1.4 Ontologies and Databases 12
1.4.1 Ontologies 12
1.4.2 Gene Ontology 13
1.4.3 Kyoto Encyclopedia of Genes and Genomes 13
1.4.4 Reactome 13
1.4.5 Brenda 14
1.4.6 DAVID 14
1.4.7 Protein Data Bank 15
1.4.8 Systems Biology Markup Language 15
1.5 Methods for Cellular Modeling 17
1.6 Summary 17
1.7 Problems 17
Bibliography 18
2 Structures of Protein Complexes and Subcellular Structures 21
2.1 Examples of Protein Complexes 22
2.1.1 Principles of Protein-Protein Interactions 24
2.1.2 Categories of Protein Complexes 27
2.2 Complexome: The Ensemble of Protein Complexes 28
2.2.1 Complexome of Saccharomyces cerevisiae 28
2.2.2 Bacterial Protein Complexomes 30
2.2.3 Complexome of Human 31
2.3 Experimental Determination of Three-Dimensional Structures of Protein Complexes 31
2.3.1 X-ray Crystallography 32
2.3.2 NMR 34
2.3.3 Electron Crystallography/Electron Microscopy 34
2.3.4 Cryo-EM 34
2.3.5 Immunoelectron Microscopy 35
2.3.6 Fluorescence Resonance Energy Transfer 35
2.3.7 Mass Spectroscopy 36
2.4 Density Fitting 38
2.4.1 Correlation-Based Density Fitting 38
2.5 Fourier Transformation 40
2.5.1 Fourier Series 40
2.5.2 Continuous Fourier Transform 41
2.5.3 Discrete Fourier Transform 41
2.5.4 Convolution Theorem 41
2.5.5 Fast Fourier Transformation 42
2.6 Advanced Density Fitting 44
2.6.1 Laplacian Filter 45
2.7 FFT Protein-Protein Docking 46
2.8 Protein-Protein Docking Using Geometric Hashing 48
2.9 Prediction of Assemblies from Pairwise Docking 49
2.9.1 CombDock 49
2.9.2 Multi-LZerD 52
2.9.3 3D-MOSAIC 52
2.10 Electron Tomography 53
2.10.1 Reconstruction of Phantom Cell 55
2.10.2 Protein Complexes in Mycoplasma pneumoniae 55
2.11 Summary 56
2.12 Problems 57
2.12.1 Mapping of Crystal Structures into EM Maps 57
Bibliography 60
3 Analysis of Protein-Protein Binding 63
3.1 Modeling by Homology 63
3.2 Properties of Protein-Protein Interfaces 66
3.2.1 Size and Shape 66
3.2.2 Composition of Binding Interfaces 68
3.2.3 Hot Spots 69
3.2.4 Physicochemical Properties of Protein Interfaces 71
3.2.5 Predicting Binding Affinities of Protein-Protein Complexes 72
3.2.6 Forces Important for Biomolecular Association 73
3.3 Predicting Protein-Protein Interactions 75
3.3.1 Pairing Propensities 75
3.3.2 Statistical Potentials for Amino Acid Pairs 78
3.3.3 Conservation at Protein Interfaces 79
3.3.4 Correlated Mutations at Protein Interfaces 83
3.4 Summary 86
3.5 Problems 86
Bibliography 86
4 Algorithms on Mathematical Graphs 89
4.1 Primer on Mathematical Graphs 89
4.2 A Few Words About Algorithms and Computer Programs 90
4.2.1 Implementation of Algorithms 91
4.2.2 Classes of Algorithms 92
4.3 Data Structures for Graphs 93
4.4 Dijkstra’s Algorithm 95
4.4.1 Description of the Algorithm 96
4.4.2 Pseudocode 100
4.4.3 Running Time 101
4.5 Minimum Spanning Tree 101
4.5.1 Kruskal’s Algorithm 102
4.6 Graph Drawing 102
4.7 Summary 104
4.8 Problems 105
4.8.1 Force Directed Layout of Graphs 107
Bibliography 110
5 Protein-Protein Interaction Networks - Pairwise Connectivity 111
5.1 Experimental High-Throughput Methods for Detecting Protein-Protein Interactions 111
5.1.1 Gel Electrophoresis 112
5.1.2 Two-Dimensional Gel Electrophoresis 112
5.1.3 Affinity Chromatography 113
5.1.4 Yeast Two-hybrid Screening 114
5.1.5 Synthetic Lethality 115
5.1.6 Gene Coexpression 116
5.1.7 Databases for Interaction Networks 116
5.1.8 Overlap of Interactions 116
5.1.9 Criteria to Judge the Reliability of Interaction Data 118
5.2 Bioinformatic Prediction of Protein-Protein Interactions 120
5.2.1 Analysis of Gene Order 121
5.2.2 Phylogenetic Profiling/Coevolutionary Profiling 121
5.2.2.1 Coevolution 122
5.3 Bayesian Networks for Judging the Accuracy of Interactions 124
5.3.1 Bayes’Theorem 125
5.3.2 Bayesian Network 125
5.3.3 Application of Bayesian Networks to Protein-Protein Interaction Data 126
5.3.3.1 Measurement of Reliability “Likelihood Ratio” 127
5.3.3.2 Prior and Posterior Odds 127
5.3.3.3 A Worked Example: Parameters of the Naïve Bayesian Network for Essentiality 128
5.3.3.4 Fully Connected Experimental Network 129
5.4 Protein Interaction Networks 131
5.4.1 Protein Interaction Network of Saccharomyces cerevisiae 131
5.4.2 Protein Interaction Network of Escherichia coli 131
5.4.3 Protein Interaction Network of Human 132
5.5 Protein Domain Networks 132
5.6 Summary 135
5.7 Problems 136
5.7.1 Bayesian Analysis of (Fake) Protein Complexes 136
Bibliography 138
6 Protein-Protein Interaction Networks - Structural Hierarchies 141
6.1 Protein Interaction Graph Networks 141
6.1.1 Degree Distribution 141
6.1.2 Clustering Coefficient 143
6.2 Finding Cliques 145
6.3 Random Graphs 146
6.4 Scale-Free Graphs 147
6.5 Detecting Communities in Networks 149
6.5.1 Divisive Algorithms for Mapping onto Tree 153
6.6 Modular Decomposition 155
6.6.1 Modular Decomposition of Graphs 157
6.7 Identification of Protein Complexes 161
6.7.1 MCODE 161
6.7.2 ClusterONE 162
6.7.3 DACO 163
6.7.4 Analysis of Target Gene Coexpression 164
6.8 Network Growth Mechanisms 165
6.9 Summary 169
6.10 Problems 169
Bibliography 178
7 Protein-DNA Interactions 181
7.1 Transcription Factors 181
7.2 Transcription Factor-Binding Sites 183
7.3 Experimental Detection of TFBS 183
7.3.1 Electrophoretic Mobility Shift Assay 183
7.3.2 DNAse Footprinting 184
7.3.3 Protein-Binding Microarrays 185
7.3.4 Chromatin Immunoprecipitation Assays 187
7.4 Position-Specific Scoring Matrices 187
7.5 Binding Free Energy Models 189
7.6 Cis-Regulatory Motifs 191
7.6.1 DACO Algorithm 192
7.7 Relating Gene Expression to Binding of Transcription Factors 192
7.8 Summary 194
7.9 Problems 194
Bibliography 195
8 Gene Expression and Protein Synthesis 197
8.1 Regulation of Gene Transcription at Promoters 197
8.2 Experimental Analysis of Gene Expression 198
8.2.1 Real-time Polymerase Chain Reaction 199
8.2.2 Microarray Analysis 199
8.2.3 RNA-seq 201
8.3 Statistics Primer 201
8.3.1 t-Test 203
8.3.2 z-Score 203
8.3.3 Fisher’s Exact Test 203
8.3.4 Mann-Whitney-Wilcoxon Rank Sum Tests 205
8.3.5 Kolmogorov-Smirnov Test 206
8.3.6 Hypergeometric Test 206
8.3.7 Multiple Testing Correction 207
8.4 Preprocessing of Data 207
8.4.1 Removal of Outlier Genes 207
8.4.2 Quantile Normalization 208
8.4.3 Log Transformation 208
8.5 Differential Expression Analysis 209
8.5.1 Volcano Plot 210
8.5.2 SAM Analysis of Microarray Data 210
8.5.3 Differential Expression Analysis of RNA-seq Data 212
8.5.3.1 Negative Binomial Distribution 213
8.5.3.2 DESeq 213
8.6 Gene Ontology 214
8.6.1 Functional Enrichment 216
8.7 Similarity of GO Terms 217
8.8 Translation of Proteins 217
8.8.1 Transcription and Translation Dynamics 218
8.9 Summary 219
8.10 Problems 220
Bibliography 224
9 Gene Regulatory Networks 227
9.1 Gene Regulatory Networks (GRNs) 228
9.1.1 Gene Regulatory Network of E. coli 228
9.1.2 Gene Regulatory Network of S. cerevisiae 231
9.2 Graph Theoretical Models 231
9.2.1 Coexpression Networks 232
9.2.2 Bayesian Networks 233
9.3 Dynamic Models 234
9.3.1 Boolean Networks 234
9.3.2 Reverse Engineering Boolean Networks 235
9.3.3 Differential Equations Models 236
9.4 DREAM: Dialogue on Reverse Engineering Assessment and Methods 238
9.4.1 Input Function 239
9.4.2 YAYG Approach in DREAM3 Contest 240
9.5 Regulatory Motifs 244
9.5.1 Feed-forward Loop (FFL) 245
9.5.2 SIM 245
9.5.3 Densely Overlapping Region (DOR) 246
9.6 Algorithms on Gene Regulatory Networks 247
9.6.1 Key-pathway Miner Algorithm 247
9.6.2 Identifying Sets of Dominating Nodes 248
9.6.3 Minimum Dominating Set 249
9.6.4 Minimum Connected Dominating Set 249
9.7 Summary 250
9.8 Problems 251
Bibliography 254
10 Regulatory Noncoding RNA 257
10.1 Introduction to RNAs 257
10.2 Elements of RNA Interference: siRNAs and miRNAs 259
10.3 miRNA Targets 261
10.4 Predicting miRNA Targets 264
10.5 Role of TFs and miRNAs in Gene-Regulatory Networks 264
10.6 Constructing TF/miRNA Coregulatory Networks 266
10.6.1 TFmiRWeb Service 267
10.6.1.1 Construction of Candidate TF-miRNA-Gene FFLs 268
10.6.1.2 Case Study 269
10.7 Summary 270
Bibliography 270
11 Computational Epigenetics 273
11.1 EpigeneticModifications 273
11.1.1 DNA Methylation 273
11.1.1.1 CpG Islands 276
11.1.2 Histone Marks 277
11.1.3 Chromatin-Regulating Enzymes 278
11.1.4 Measuring DNA Methylation Levels and Histone Marks Experimentally 279
11.2 Working with Epigenetic Data 281
11.2.1 Processing of DNA Methylation Data 281
11.2.1.1 Imputation of Missing Values 281
11.2.1.2 Smoothing of DNA Methylation Data 281
11.2.2 Differential Methylation Analysis 282
11.2.3 Comethylation Analysis 283
11.2.4 Working with Data on Histone Marks 285
11.3 Chromatin States 286
11.3.1 Measuring Chromatin States 286
11.3.2 Connecting Epigenetic Marks and Gene Expression by Linear Models 287
11.3.3 Markov Models and Hidden Markov Models 288
11.3.4 Architecture of a Hidden Markov Model 290
11.3.5 Elements of an HMM 291
11.4 The Role of Epigenetics in Cellular Differentiation and Reprogramming 292
11.4.1 Short History of Stem Cell Research 293
11.4.2 Developmental Gene Regulatory Networks 293
11.5 The Role of Epigenetics in Cancer and Complex Diseases 295
11.6 Summary 296
11.7 Problems 296
Bibliography 301
12 Metabolic Networks 303
12.1 Introduction 303
12.2 Resources on Metabolic Network Representations 306
12.3 Stoichiometric Matrix 308
12.4 Linear Algebra Primer 309
12.4.1 Matrices: Definitions and Notations 309
12.4.2 Adding, Subtracting, and Multiplying Matrices 310
12.4.3 Linear Transformations, Ranks, and Transpose 311
12.4.4 Square Matrices and Matrix Inversion 311
12.4.5 Eigenvalues of Matrices 312
12.4.6 Systems of Linear Equations 313
12.5 Flux Balance Analysis 314
12.5.1 Gene Knockouts: MOMA Algorithm 316
12.5.2 OptKnock Algorithm 318
12.6 Double Description Method 319
12.7 Extreme Pathways and Elementary Modes 324
12.7.1 Steps of the Extreme Pathway Algorithm 324
12.7.2 Analysis of Extreme Pathways 328
12.7.3 Elementary Flux Modes 329
12.7.4 Pruning Metabolic Networks: NetworkReducer 331
12.8 Minimal Cut Sets 332
12.8.1 Applications of Minimal Cut Sets 337
12.9 High-Flux Backbone 339
12.10 Summary 341
12.11 Problems 341
12.11.1 Static Network Properties: Pathways 341
Bibliography 346
13 Kinetic Modeling of Cellular Processes 349
13.1 Biological Oscillators 349
13.2 Circadian Clocks 350
13.2.1 Role of Post-transcriptional Modifications 352
13.3 Ordinary Differential Equation Models 353
13.3.1 Examples for ODEs 354
13.4 Modeling Cellular Feedback Loops by ODEs 356
13.4.1 Protein Synthesis and Degradation: Linear Response 356
13.4.2 Phosphorylation/Dephosphorylation - Hyperbolic Response 357
13.4.3 Phosphorylation/Dephosphorylation - Buzzer 359
13.4.4 Perfect Adaptation - Sniffer 360
13.4.5 Positive Feedback - One-Way Switch 361
13.4.6 Mutual Inhibition - Toggle Switch 362
13.4.7 Negative Feedback - Homeostasis 362
13.4.8 Negative Feedback: Oscillatory Response 364
13.4.9 Cell Cycle Control System 365
13.5 Partial Differential Equations 366
13.5.1 Spatial Gradients of Signaling Activities 368
13.5.2 Reaction-Diffusion Systems 368
13.6 Dynamic Phosphorylation of Proteins 369
13.7 Summary 370
13.8 Problems 372
Bibliography 373
14 Stochastic Processes in Biological Cells 375
14.1 Stochastic Processes 375
14.1.1 Binomial Distribution 376
14.1.2 Poisson Process 377
14.1.3 Master Equation 377
14.2 Dynamic Monte Carlo (Gillespie Algorithm) 378
14.2.1 Basic Outline of the Gillespie Method 379
14.3 Stochastic Effects in Gene Transcription 380
14.3.1 Expression of a Single Gene 380
14.3.2 Toggle Switch 381
14.4 Stochastic Modeling of a Small Molecular Network 385
14.4.1 Model System: Bacterial Photosynthesis 385
14.4.2 Pools-and-Proteins Model 386
14.4.3 Evaluating the Binding and Unbinding Kinetics 387
14.4.4 Pools of the Chromatophore Vesicle 389
14.4.5 Steady-State Regimes of the Vesicle 389
14.5 Parameter Optimization with Genetic Algorithm 392
14.6 Protein-Protein Association 395
14.7 Brownian Dynamics Simulations 396
14.8 Summary 398
14.9 Problems 400
14.9.1 Dynamic Simulations of Networks 400
Bibliography 407
15 Integrated Cellular Networks 409
15.1 Response of Gene Regulatory Network to Outside Stimuli 410
15.2 Whole-Cell Model of Mycoplasma genitalium 412
15.3 Architecture of the Nuclear Pore Complex 416
15.4 Integrative Differential Gene Regulatory Network for Breast Cancer
Identified Putative Cancer Driver Genes 416
15.5 Particle Simulations 421
15.6 Summary 423
Bibliography 424
16 Outlook 427
Index 429
