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More About This Textbook
Overview
A comprehensive look at empirical approaches to molecular discovery, their relationships with rational design, and the future of both
Empirical methods of discovery, along with serendipitous and rational design approaches, have played an important role in human history. Searching for Molecular Solutions compares empirical discovery strategies for biologically useful molecules with serendipitous discovery and rational design, while also considering the strengths and limitations of empirical pathways to molecular discovery.
Logically arranged, this text examines the different modes of molecular discovery, empha-sizing the historical and ongoing importance of empirical strategies. Along with a broad overview of the subject matter, Searching for Molecular Solutions explores:
Searching for Molecular Solutions covers several major areas of modern research, development, and practical applications of molecular sciences. This text offers empirical-rational principles of broad relevance to scientists, professionals, and students interested in general aspectsof molecular discovery, as well as the thought processes behind experimental approaches.
Note: CD-ROM/DVD and other supplementary materials are not included as part of eBook file.
Editorial Reviews
Doody's Review Service
Reviewer: Omer Iqbal, MD, FACC, FESC (Loyola University Medical Center)Description: This useful book covers several major areas of modern research, development, practical applications of molecular science, and different modes of molecular discovery, emphasizing the historical and ongoing importance of empirical strategies.
Purpose: The aim is to make the case that finding useful molecules is far from simple and that empirical strategies will complement and even outperform rational approaches in many areas for the foreseeable future. The essential aim is to compare different modes of molecular discovery, with an emphasis on the historical and ongoing importance of empirical strategies.
Audience: The author intends this book for scientists, professionals, and students interested in the general aspects of molecular discovery, as well as the thought processes behind experimental approaches.
Features: The book begins with a very informative introduction to molecules. The 10 chapters deal with the differing modes of molecular discovery; biological precedents for evolutionary approaches; enzyme evolution and design; functional nucleic acid discovery; antibodies and other recognition molecules; general aspects of molecular recognition; small molecule discovery approaches; rational molecular design; the interplay between empirical and rational strategies; and their ongoing roles in the future of molecular discovery. The book is beautifully illustrated.
Assessment: This is a valuable resource that compares empirical discovery and rational design, while also considering the strengths and limitations of empirical pathways to molecular discovery. Scientists, professionals, and students interested in general aspects of molecular discovery will find this book extremely useful.
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Table of Contents
Acknowledgments xi
Introduction xni
1 If It Works, It Works: Pragmatic Molecular Discovery 1
Overview 1
Three Ways of Discovery 1
The Three Wise (Serendipitous) Men and Other Stories 1
An Empirical Fable 2
Productively Applying Empiricism 3
Screening Versus Selection 4
How to be a Librarian 6
Demon-strating the Power of Empirical Screening and Selection 11
Dreaming of Pandemonium: a Universal Molecular Space 13
Modes of Molecular Discovery 16
The Borderland of Rational Design 17
2 Empirical Miracles: Nature's Precedents for Empirical Solutions 22
Overview 22
Evolution Itself 22
Evolution: Natural and Artificial 25
To Opine on Design 26
Natural Evolution at Work 26
The Raw Materials: Diversity Enough and Time 26
GOD from Mutation 26
GOD from Recombination and Other Things 29
A Sexual Interlude 3
Doubling Up and Reassorting 34
Lateral Thinking 36
The Process: Old Ideas and Newer Wrinkles 39
The Marks of Lamarck? 39
Evolution by Order? 42
Orderly Beginnings 43
The Arrow of Complexity? 44
Drivers of Complexity 46
Complexity and Molecular Discovery 47
Molecules of Evolution and Design Boundaries 48
Evolving Proteins 49
Enzymatic Bounty 53
Combinatorial Catalysis and Its Helpers 54
Enzymes to the Limit 56
Absent by Irreducibility, or Lack of an Access Route? 57
Food for Evolutionary Thought 59
3 Evolution's Gift: Natural Somatic Diversification and Molecular Design 61
Overview 61
Immune Systems: a Biological Fundamental 61
The Selfish Scheme 62
The Xenobiotic "Immune System" and Beyond 63
Innately Selfish 64
How to Shoot Moving Targets 66
The Empirical Basis of theAdaptive Immune System 68
The Evolved GOD of the Adaptive Immune System 71
The T Cell Repertoire and Its Special GOD 75
The Range and Utility of Adaptive Immunity 80
Antibodies and Molecular Recognition in General 81
Selfishness Revisited 84
Antibody Libraries and Iterative Selection: Natural and Artificial 88
Iteratively Speaking 89
Such Selfish Systems Send Selfless Sermons: The Largesse of Immune Systems 91
GOD in the Brain and Its Extensions 91
Molecular Sensing 93
A Bittersweet Worldview 94
Smelling a Rat, and Many Other Things 97
Multirecogmtion 98
Messages in Biological Molecular Recognition and Empirical Design 99
4 Evolution While You Wait 103
Overview 103
Putting Evolution to Work 103
Levels of Selectable Replicators 104
The Scope and Implementation of Evolution as a Workhorse 105
God in the Laboratory 10
Mutations at Will 108
Sex for Biotechnologists 111
Artificial Evolution Becomes HOT 115
Evolution on the Laboratory Bench 117
Screen (Properly) and Ye Shall Find 117
A Highly Rational Empirical Process 120
Mutations and Libraries 124
Crossing the Valley of the Shadow of Low Fitness: Journeys across Molecular Spaces 127
Colorful Neutral Springboards 129
Punctuating Sequence Space, Naturally or Otherwise 130
The Power of Display 132
Show Me Your Coat: Phage on Display 135
Display Without Cells: Doing It In Vitro 137
Making Compartments 141
Test It, Replicate It, Evolve It 144
5 The Blind Protein Maker 145
Overview 145
Applying Natural Protein Evolution Principles 146
Productively Playing with Enzymes 147
Room for Improvement 147
Tougher Enzymes 148
Better Enzymes 152
Altered and Novel Enzymes 155
Enzymes from Scratch 159
De Novo Protein Design the Empirical Way 163
Return to the Fold 163
Alphabets and Patterning 168
Finding and Evolving Folds 172
De Novo Enzymes 173
Natural and Unnatural Acts 174
Unnatural Insertions 177
In Vitro opportunities 180
New Codes in Vivo 182
Unnatural Rewards and Limits 185
6 The Blind Shaper of Nucleic Acids 187
Overview 187
Functional Nucleic Acids and their Directed Evolution 187
Early Days 187
Protein-Free Enzymes 188
Finding Functional RNAs 190
Novel Ribozymes 193
Ribozyme Replication and Other Things 193
Comparisons with Proteins 196
Aiming for Stability 196
Recombination: Still Good for RNA? 198
Folding in Two Worlds 199
Working with the Ribozyme Repertoire 202
Calling for Cofactors 204
Alphabetic Acrobatics 205
Angling for Aptamers with Aptitude 208
DNA Can Do It Too 212
Natural Aptamers and Riboswitches 213
An Aptamerican Adventure 216
Allosteric Ribozymes and Aptamers 217
Payoffs from Functional Nucleic Acids 219
Aptamer Tools: Better than Antibodies? 219
Moving Aptamers Toward the Clinic 221
Extending the Functional Range of Nucleic Acids 223
Extended Alphabets 224
The Virtual Molecular Museum 224
Altered Backbones 227
The Best of Both Worlds? 232
7 Evolving and Creating Recognition Molecules
Overview 234
The Immune System in a Bottle and on a Leash 235
New Wrinkles on the Old Way to Antibodies 235
Antibodies and Libraries 239
The GOD of Small Things: Minimizing Antibodies 245
Antibodies as Catalysts 246
Alternatives to Antibodies 252
Other Protein Scaffolds for Molecular Recognition 253
Finding and Designing Proteins for Diversification 254
Molecular Imprinting: Making its Mark 258
Imprinting of Macromolecules 264
Comparing Recognition Alternatives 266
Generalizing to Foldamers 271
8 Molecules Small and Large 275
Overview 275
As Small as Possible, but No Smaller 276
Small and Natural, Small and Useful 276
How to Find New Drugs 282
Know Your NME 282
Aiming in the Right Direction 284
Druggable Struggles 285
High-throughput Put Through High Loops 286
Chemical Libraries and the GOD of Small Molecules 287
Generalities and the Natural Approach 287
Make Your Own Library 290
Frag-mental Inspiration 294
Self-Assembling Molecular Combinatorics 297
Codes for Small Molecules 299
Tag Team Technology: Encoded Combinatorial Chemistry 300
Marrying Chemistry and Biology with Tags 304
An Evolutionary Analogy 310
From Small to Large and Back Again 314
9 An Empirical-Rational Loop Forwards 315
Overview 315
Approaching Rational Design 315
Scope of Rational Design 315
Pathways to Rational Design 319
Quantum Chemistry and Rational Design 319
Small Molecules the Rational Way 320
Virtual Virtues 323
The De Novo Ultimate? 325
Proteins by the Book 326
Getting Folding Right 327
Making Rational Predictions 329
Making Rational Proteins 331
Designer Nucleic Acids 335
Systems, Pathways, and Networks 337
10 Exploring the Limits 343
Overview 343
The Limits of Rational Design 343
Rational Design and Determinism 344
Bootstrapping and Interplay 347
Reverse-engineering Biocomplexity for Design Insights 347
Time, Knowledge, and Molecules 349
Outer Boundaries 351
Patterns for the Future 353
Primordial Alphabet Soup 353
On Molecular Translations 356
Effectors and Replicators 358
The Universal Power of Combinatorics 360
A Kaleidoscopic View 362
Glossary 365
Bibliography 374
References in Figure Legends 440
Index 443