Introduction to Bioinformatics /

Chapter 1 The Data: Storage and Retrieval................................... ................. I
G lo ssary ..................................................................................................................... 1
1.1 B asic P rinciples.............................................................................................. 2
1.2 T he D ata .......................................................................... ..................... 3
1.2.1 The Postgenomic Era.........................................................................3
1.2.2 Nucleic Acid Data Banks....................................................................6
1.2.3 Protein Sequence Data Banks..............................................................7
1.2.4 Protein Structure Databases ............................................................... 14
1.2.5 Protein Interaction Databases ...................................... ........ 16
1.2.6 Derived Data Banks ............................................................... 17
1.2.7 Integration of Databases ........................................ ......................... 18
1.3 D ata Q uality ................................................................................................... 18
1.4 Data Representation ............................................................. .......... 18
1.4.1 Protein Architecture .............................................................. ... 20
R eferences..................................................................... ...................................... 24
P roblem s ...................................................................... ....................................... 2 6
Chapter 2 Genome Sequence Analysis.................................. ........................... 29
G lo ssary ........................ ... ... ......... .................................. .................................... 29
2.1 Basic Concepts......................................................................................... 30
2.2 Genome Sequencing ................................................................ ............31
2.3 Finding the Genes ................................. ....... 32
2.4 Statistical Methods to Search for Genes ...................................... .... . 34
2.4.1 Site-Specific Scoring Matrices................................ ........... 34
2.4.2 Artificial Neural Networks............................................................... 37
2.4.3 M arkov Models and Hidden Markov Models................................. 40
2.4.4 Levels of Reliability ..........................................................................45
2.5 Comparative Genomics............................................... .....................47
2.6 A Virtual W indow on Genomes: The World W ide Web............................. 48
References.............. ......... ........................................................................49
Problems .............................................................................................................50
Chapter 3 Protein Evolution ..................................................................53
G lo ssary ......................................................................... .......................................... 5 3
3.1 Basic Concepts .............................................................................................53
3.2 Molecular Evolution............ .. ......................................... 54
3.3 How to Align Two Similar Sequences ........................................................ 55
3.4 Similarity Matrices....................................... 58
3.4.1 PAM M atrices ....................................................................... 59
3.4.2 BLOSUM M atrices ................................................................ ... 60
3.5 Penalties for Insertions and Deletions..........................................................61
3.6 The Alignment Algorithm ..................................................................61
3.7 M ultiple Alignments ........................................................................ 66
3.7.1 How to Add Sequences to a Pre-Existing Alignment.......................70
3.8 Phylogenetic Trees ....................................................................................... 71
R eferences..................................................................... ...................................... 7 3
P roblem s ..................................................................... ....................................... 74
Chapter 4 Similarity Searches in Databases...................................................... 77
Glossary ............................................................................................................. 77
4.1 Basic Principles .............................................................. ........... 77
4.2 The M ethods .............................................................. ............ 78
4.2.1 FASTA .................................... ......79
4.2.2 BLAST ................................................................ ........................... 83
4.2.3 Profile Searches.................................................................... 86
4.2.4 PSI-BLAST ..................................... .................................. 87
R eferences .................... ............................................................................................. 89
P rob lem s ...................................................................... ....................................... 9 0
Chapter 5 Amino Acid Sequence Analysis .......................................................93
G lo ssary ..................................................... .............. . .............................. ...............9 3
5 .1 B asic P rinciples..................................................................................... 9 3
5.1.1 Is It Really an Orphan Sequence?...................................................94
5.2 Search for Sequence Patterns ........................................................................95
5.3 Feature Extraction .......................................................................................... 96
5.4 Secondary Structure: Part One .....................................................................96
R eferences ...................................... ........ ...... .......... ........ ..... ............................... ..9 8
P rob lem s ......................................................... ................. ................................. 9 9
Chapter 6 Prediction of the Three-Dimensional Structure of a Protein....... 103
Glossary ..... ... ....... ................................................ ................. 103
6.1 Basic Principles ......................................................................... 103
6.2 The CASP Experiment................................................................................. 105
6.3 Secondary Structure Prediction: Part Two.................................. 107
6.4 Long-Range Contact Prediction............................. 109
6.5 Predicting Molecular Complexes: Docking M ethods .............................. 110
R eferen ces ........................................................................ ................................... Il l
Problems ................................................................. .......................................... ....... 113
Chapter 7 Homology M odeling ........................................................................ 115
Glossary .............. .................. ................... .......................................... 115
7. 1 Basic Principles.......................................................................................... 115
7.2 The Steps of Comparative Modeling............................. 117
7.2.1 Template Selection .................... ........... . ............................. .. 118
7.2.2 Sequence Alignment ..................................... 119
7.2.3 Loops ............................................................................................. 121
7.2.4 Side Chain M odeling ..................................................................... 124
7.2.5 M odel Optim ization ..................................... 125
7.3 Accuracy of Hom ology M odels .................................................................. 126
7.4 M anual versus Autom atic M odels ..................................... 126
7.5 Practical Notes ............................................................................................. 126
7.6 Sum ming Up... .................................................................................... 129
References............................................................................................................... 131
Problem s ............................... .......................................... 134
Chapter 8 Fold Recognition M ethods......................... . ............. 137
Glossary ................................................................................................................. 137
8. 1 Basic Principles............................................................ .......... 137
8.2 Profile-Based M ethods ..................................................................... 138
8.3 Threading M ethods ...................................................................................... 140
8.4 The Fold Library ........................................................................ 142
8.5 How Well Do These Methods Work?..................................... 142
References.................................................................... ..................................... 143
Problem s ................................................................................................................ 143
Chapter 9 New Fold Modeling ..................................... 147
Glossary ...................................................................................... ............................. 147
9.1 Basic Principles........................................................................ 147
9.2 Estimating the Energy of a Protein Conformation..................... 148
9.3 Energy M inim ization ........................................................... .................. 150
9.4 M olecular Dynam ics ................................................................................. 151
9.4.1 The M onte Carlo M ethod ..................................... 153
9.4.2 Genetic Algorithm s .......................................................................... 154
9.4.3 Combined M ethodologies ..................................... 156
References....................................................................... ....................................... 156
Problem s ................................................................................................................ 157
Chapter 10 The "Om ics" Universe.............................................................. 159
10.1 Basic Principles................ ......................................... ........... 159
10.2 Transcriptom ics ........................................ 159
10.3 Proteom ics ................................... ........................... . ............ 162
10.4 Interactomics ........................................ 165
10.5 Structural Genomics................................ 166
10.6 Pharmacogenomics........................ 166
10.7 But This Is Not All... ...................................... 168