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Structural Bioinformatics, 2nd Edition

Book Description

Structural Bioinformatics was the first major effort to show the application of the principles and basic knowledge of the larger field of bioinformatics to questions focusing on macromolecular structure, such as the prediction of protein structure and how proteins carry out cellular functions, and how the application of bioinformatics to these life science issues can improve healthcare by accelerating drug discovery and development. Designed primarily as a reference, the first edition nevertheless saw widespread use as a textbook in graduate and undergraduate university courses dealing with the theories and associated algorithms, resources, and tools used in the analysis, prediction, and theoretical underpinnings of DNA, RNA, and proteins.

This new edition contains not only thorough updates of the advances in structural bioinformatics since publication of the first edition, but also features eleven new chapters dealing with frontier areas of high scientific impact, including: sampling and search techniques; use of mass spectrometry; genome functional annotation; and much more.

Offering detailed coverage for practitioners while remaining accessible to the novice, Structural Bioinformatics, Second Edition is a valuable resource and an excellent textbook for a range of readers in the bioinformatics and advanced biology fields.

Praise for the previous edition:

"This book is a gold mine of fundamental and practical information in an area not previously well represented in book form."

—Biochemistry and Molecular Education

"... destined to become a classic reference work for workers at all levels in structural bioinformatics...recommended with great enthusiasm for educators, researchers, and graduate students."

—BAMBED

"...a useful and timely summary of a rapidly expanding field."

—Nature Structural Biology

"...a terrific job in this timely creation of a compilation of articles that appropriately addresses this issue."

—Briefings in Bioinformatics

Table of Contents

  1. Cover
  2. Title Page
  3. Copyright
  4. Foreword
  5. Contributors
  6. Section I DATA COLLECTION, ANALYSIS, AND VISUALIZATION
    1. 1 DEFINING BIOINFORMATICS AND STRUCTURAL BIOINFORMATICS
      1. WHAT IS BIOINFORMATICS?
      2. TECHNICAL CHALLENGES WITHIN STRUCTURAL BIOINFORMATICS
      3. INTEGRATING STRUCTURAL DATA WITH OTHER DATA SOURCES
      4. REFERENCES
    2. 2 FUNDAMENTALS OF PROTEIN STRUCTURE
      1. THE IMPORTANCE OF PROTEIN STRUCTURE
      2. THE PRIMARY STRUCTURE OF PROTEINS: THE AMINO ACID SEQUENCE
      3. THE SECONDARY STRUCTURE OF PROTEINS: THE LOCAL THREE-DIMENSIONAL STRUCTURE
      4. THE TERTIARY STRUCTURE OF PROTEINS: THE GLOBAL THREE-DIMENSIONAL STRUCTURE
      5. THE QUATERNARY STRUCTURE OF PROTEINS: ASSOCIATIONS OF MULTIPLE POLYPEPTIDE CHAINS
      6. CONCLUSION
      7. MORE INFORMATION ON THE INTERNET
      8. REFERENCES
    3. 3 FUNDAMENTALS OF DNA AND RNA STRUCTURE
      1. INTRODUCTION
      2. CHEMICAL STRUCTURE OF NUCLEIC ACIDS
      3. BASE-PAIR GEOMETRY
      4. CONFORMATION OF THE SUGAR PHOSPHATE BACKBONE
      5. STRUCTURES OF NUCLEIC ACIDS
      6. CONCLUSION
      7. ACKNOWLEDGMENTS
      8. REFERENCES
    4. 4 COMPUTATIONAL ASPECTS OF HIGH-THROUGHPUT CRYSTALLOGRAPHIC MACROMOLECULAR STRUCTURE DETERMINATION
      1. INTRODUCTION
      2. HIGH-THROUGHPUT STRUCTURE DETERMINATION
      3. DATA ANALYSIS
      4. HEAVY ATOM LOCATION AND COMPUTATION OF EXPERIMENTAL PHASES
      5. DENSITY MODIFICATION
      6. MOLECULAR REPLACEMENT
      7. REFINEMENT
      8. VALIDATION
      9. CHALLENGES TO AUTOMATION
      10. CONCLUSIONS
      11. REFERENCES
    5. 5 MACROMOLECULAR STRUCTURE DETERMINATION BY NMR SPECTROSCOPY
      1. INTRODUCTION TO PROTEIN STRUCTURE DETERMINATION BY NMR
      2. PREPARATION OF PROTEIN SAMPLES FOR NMR
      3. PROTOCOL FOR PROTEIN STRUCTURE DETERMINATION BY NMR
      4. PROBA BILISTIC APPROACHES AND AUTOMATION
      5. DATABASES FOR BIOMOLECULAR NMR
      6. ACKNOWLEDGMENTS
      7. REFERENCES
    6. 6 ELECTRON MICROSCOPY IN THE CONTEXT OF STRUCTURAL SYSTEMS BIOLOGY
      1. INTRODUCTION
      2. ELECTRON OPTICS AND IMAGE FORMATION
      3. THREE-DIMENSIONAL RECONSTRUCTION
      4. COMBINATION WITH OTHER APPROACHES: HYBRID METHODS
      5. FUTURE DIRECTIONS
      6. ACKNOWLEDGMENTS
      7. REFERENCES
    7. 7 STUDY OF PROTEIN THREE-DIMENSIONAL STRUCTURE AND DYNAMICS USING PEPTIDE AMIDE HYDROGEN/ DEUTERIUM EXCHANGE MASS SPECTROMETRY (DXMS) AND CHEMICAL CROSS-LINKING WITH MASS SPECTROMETRY TO CONSTRAIN MOLECULAR MODELING
      1. INTRODUCTION
      2. OVERVIEW OF DXMS METHODOLOGY
      3. EXAMPLES OF APPLICATIONS OF DXMS
      4. DXMS ANALYSIS: CONCLUDING REMARKS
      5. HYBRID BIOCHEMICAL/BIOINFORMATICS APPROACH TO LOWRESOLUTION STRUCTURE DETERMINATION USING CHEMICAL CROSS-LINKERS AND MASS SPECTROMETRY
      6. RECENT APPLICATIONS
      7. CONCLUSION WITH RESPECT TO CHEMICAL CROSS-LINKAGE METHODS
      8. ACKNOWLEDGMENTS
      9. REFERENCES
    8. 8 SEARCH AND SAMPLING IN STRUCTURAL BIOINFORMATICS
      1. INTRODUCTION
      2. SAMPLING STRUCTURAL SPACE
      3. SEARCH METHODS
      4. DATA ANALYSIS AND REDUCTION
      5. CONCLUDING REMARKS
      6. ACKNOWLEDGMENTS
      7. REFERENCES (Including Remarks on Recommended Further Reading)
    9. 9 MOLECULAR VISUALIZATION
      1. INTRODUCTION
      2. THE PROCESS OF MOLECULAR VISUALIZATION
      3. MOLECULAR MODELS
      4. MOLECULAR VISUALIZATION PROGRAMS
      5. REFERENCES
  7. Section II DATA REPRESENTATION AND DATABASES
    1. 10 THE PDB FORMAT, mmCIF FORMATS, AND OTHER DATA FORMATS
      1. INTRODUCTION
      2. THE PDB FORMAT
      3. mmCIF: A DICTIONARY-BASED APPROACH TO DATA DESCRIPTION
      4. THE PDB EXCHANGE AND OTHER DATA DICTIONARIES
      5. SUPPORTING OTHER FORMATS
      6. SUPPORTING APPLICATION PROGRAM INTERFACES
      7. CONCLUSION
      8. ACKNOWLEDGMENTS
      9. REFERENCES
    2. 11 THE WORLDWIDE PROTEIN DATA BANK
      1. INTRODUCTION
      2. DATA ACQUISITION AND PROCESSING
      3. DATA ACCESS
      4. RCSB PDB
      5. PDBj
      6. PDBe
      7. BMRB
      8. FUTURE
      9. ACKNOWLEDGMENTS
      10. REFERENCES
    3. 12 THE NUCLEIC ACID DATABASE
      1. INTRODUCTION
      2. DATA PROCESSING AND VALIDATION
      3. THE DATABASE
      4. DISTRIBUTION OF INFORMATION
      5. APPLICATIONS OF THE NDB
      6. ACKNOWLEDGMENT
      7. REFERENCES
    4. 13 OTHER STRUCTURE-BASED DATABASES
      1. INTRODUCTION
      2. THE ADDED VALUE PHILOSOPHY
      3. OTHER PRIMARY INFORMATION RESOURCES
      4. SECONDARY RESOURCES
      5. STRUCTURAL DATABASES OF THE FUTURE
      6. REFERENCES
  8. Section III DATA INTEGRITY AND COMPARATIVE FEATURES
    1. 14 STRUCTURAL QUALITY ASSURANCE
      1. INTRODUCTION
      2. STRUCTURES AS MODELS
      3. AIMS
      4. ERROR ESTIMATION AND PRECISION
      5. ERROR ESTIMATES IN X-RAY CRYSTALLOGRAPHY
      6. ERROR ESTIMATES IN NMR SPECTROSCOPY
      7. ERRORS IN DEPOSITED STRUCTURES
      8. STEREOCHEMICAL PARAMETERS
      9. SOFTWARE FOR QUALITY CHECKS
      10. PROCHECK
      11. WHAT_CHECK
      12. QUALITY INFORMATION ON THE WEB
      13. PDBREPORT–WHAT_CHECK Results
      14. CONCLUSIONS
      15. ACKNOWLEDGMENTS
      16. REFERENCES
    2. 15 THE IMPACT OF LOCAL ACCURACY IN PROTEIN AND RNA STRUCTURES: VALIDATION AS AN ACTIVE TOOL
      1. INTRODUCTION
      2. METHODOLOGY OF ALL-ATOM CONTACT ANALYSIS
      3. COMPLEMENTARY RELATIONSHIP WITH MORE TRADITIONAL CRITERIA
      4. USING MOLPROBITY AND RELATED FACILITIES
      5. RNA: VALIDATION, STRUCTURE IMPROVEMENT, AND CONFORMER STRINGS
      6. USING LOCAL ACCURACY IN BIOINFORMATIC ANALYSES
      7. RELEVANT WEB SITES
      8. REFERENCES
    3. 16 STRUCTURE COMPARISON AND ALIGNMENT
      1. INTRODUCTION
      2. GENERAL APPROACH TO STRUCTURE COMPARISON AND ALIGNMENT
      3. COMPARISON ALGORITHM AND OPTIMIZATION
      4. HOW WELL ARE WE DOING?
      5. SAMPLE RESULTS FROM STRUCTURE COMPARISON AND ALIGNMENT
      6. MULTIPLE STRUCTURE ALIGNMENT
      7. FLEXIBLE STRUCTURE ALIGNMENT
      8. MAPPING PROTEIN FOLD SPACE
      9. THE IMPACT OF STRUCTURAL GENOMICS
      10. THE FUTURE
      11. ACKNOWLEDGMENTS
      12. REFERENCES
    4. 17 PROTEIN STRUCTURE EVOLUTION AND THE SCOP DATABASE
      1. INTRODUCTION
      2. THE EVOLUTION OF PROTEINS
      3. THE EVOLUTION OF FOLD
      4. THE EVOLUTION OF ENZYMATIC CATALYSIS
      5. THE COMPARISON OF STRUCTURES
      6. SCOP HIERARCHY
      7. CLASSES
      8. FOLDS
      9. SUPERFAMILIES
      10. FAMILIES
      11. ORGANIZATION AND CAPABI LITIES OF THE SCOP RESOURCE
      12. BROWSING THROUGH THE SCOP HIERARCHY
      13. LINKING TO OTHER STRUCTURE AND SEQUENCE DATABASES
      14. SCOP REFINEMENTS TO ACCOMMODATE STRUCTURAL GENOMICS
      15. NEW FEATURES IN SCOP
      16. INTEGRATION WITH OTHER DATABASES
      17. RECLASSIFICATION
      18. SCOP USAGE
      19. SCOP FROM A USER’S PERSPECTIVE
      20. REFERENCES
    5. 18 THE CATH DOMAIN STRUCTURE DATABASE
      1. INTRODUCTION
      2. HISTORICAL DEVELOPMENT
      3. CURRENT METHODOLOGIES FOR IDENTIFYING STRUCTURAL SIMILARITIES AND EVOLUTIONARY RELATIONSHIPS IN CATH
      4. CLASSIFYING CLOSE HOMOLOGUES (CHOPCLOSE)
      5. IDENTIFICATION OF DOMAIN BOUNDARIES
      6. METHODS TO DETECT SEQUENCE AND STRUCTURAL RELATIVES
      7. STRUCTURE-BASED METHODS FOR IDENTIFYING STRUCTURAL HOMOLOGUES AND RELATED FOLDS (SSAP AND CATHEDRAL)
      8. SSAP—SEQUENTIAL STRUCTURE ALIGNMENT PROGRAM
      9. CATHEDRAL—CATHS EXISTING DOMAIN RECOGNITION ALGORITHM
      10. METHODS FOR GENERATING MULTIPLE STRUCTURE ALIGNMENTS (CORA) AND PROTOCOLS FOR USING 3D TEMPLATES USED TO IDENTIFY DISTANT STRUCTURAL RELATIONSHIPS
      11. SEQUENCE, STRUCTURAL, AND FUNCTIONAL VALIDATION OF HOMOLOGY
      12. THE DICTIONARY OF HOMOLOGOUS SUPERFAMILIES (DHS)
      13. THE GENE3D RESOURCE
      14. THE CATH WEB SITE AND SERVER
      15. THE CATHEDRAL SERVER
      16. IS FOLD CLASSIFICATION A LEGITIMATE REPRESENTATION OF DOMAIN STRUCTURE SPACE?
      17. POPULATION OF SUPERFAMILIES AND FAMILIES WITHIN FOLDS
      18. FOLD CLASSIFICATION IN CATH
      19. ACKNOWLEDGMENTS
      20. REFERENCES
  9. Section IV STRUCTURAL AND FUNCTIONAL ASSIGNMENT
    1. 19 SECONDARY STRUCTURE ASSIGNMENT
      1. SECONDARY STRUCTURE CONCEPTS
      2. ASSIGNMENT METHODS
      3. SECONDARY STRUCTURE STATISTICS AND COMPARISON
      4. APPLICATIONS OF SECONDARY STRUCTURE
      5. CONCLUSION
      6. ABBREVIATIONS
      7. ACKNOWLEDGMENTS
      8. REFERENCES
    2. 20 IDENTIFYING STRUCTURAL DOMAINS IN PROTEINS
      1. INTRODUCTION
      2. DEFINITIONS OF STRUCTURAL DOMAINS
      3. ALGORITHMS FOR IDENTIFYING STRUCTURAL DOMAINS: INSIGHT INTO HISTORY AND METHODOLOGY
      4. ALGORITHMS FOR IDENTIFYING STRUCTURAL DOMAINS: IN-DEPTH
      5. DOMAIN ASSIGNMENTS: EVALUATING AUTOMATIC METHODS
      6. DOMAIN PREDICTION BASED ON SEQUENCE INFORMATION
      7. CONCLUSIONS AND PERSPECTIVES
      8. WEB RESOURCES
      9. REFERENCES
    3. 21 INFERRING PROTEIN FUNCTION FROM STRUCTURE
      1. INTRODUCTION
      2. WHAT INFORMATION CAN BE OBTAINED FROM THREE-DIMENSIONAL PROTEIN STRUCTURES?
      3. INFERRING FUNCTION FROM STRUCTURE
      4. STRUCTURAL GENOMICS: HIGH-THROUGHPUT FUNCTION PREDICTION
      5. CONCLUSIONS
      6. REFERENCES
    4. 22 STRUCTURAL ANNOTATION OF GENOMES
      1. INTRODUCTION
      2. AVAILABILITY OF COMPLETED GENOMES
      3. METHODOLOGIES FOR IDENTIFYING STRUCTURAL PROTEIN DOMAINS IN GENOMES
      4. HOW WELL ARE GENOMES COVERED BY STRUCTURAL DOMAIN ANNOTATION?
      5. CAN WE DETERMINE ALL THE STRUCTURES PRESENT IN THE GENOMES?—STRUCTURAL ANNOTATION OF GENOMES AND STRUCTURAL GENOMICS
      6. WHAT CAN STRUCTURAL GENOME ANNOTATION TELL US ABOUT EVOLUTION?
      7. STRUCTURAL GENOME ANNOTATION RESOURCES
      8. SUPERFAMILY
      9. 3D GENOMICS
      10. SUMMARY
      11. REFERENCES
    5. 23 EVOLUTION STUDIED USING PROTEIN STRUCTURE
      1. STRUCTURES AS EVOLUTIONARY UNITS
      2. PHYLOGENY BY PROTEIN DOMAIN CONTENT
      3. THE LAST UNIVERSAL COMMON ANCESTOR (LUCA)
      4. ANCIENT GEOCHEMICAL ENVIRONMENT REFLECTED BY THE MODERN STRUCTURE REPERTOIRE
      5. THE EVOLUTIONARY HISTORY OF PROTEIN DOMAINS
      6. FILLING IN FOLD SPACE: CURRENT LIMITATIONS
      7. CONCLUSION
      8. REFERENCES
  10. Section V MACROMOLECULAR INTERACTIONS
    1. 24 ELECTROSTATIC INTERACTIONS
      1. INTRODUCTION
      2. OVERVIEW OF FUNCTIONAL ROLES OF ELECTROSTATICS
      3. BRIEF HISTORY
      4. THE NEED FOR MORE EFFICIENT AND SCALABLE ELECTROSTATICS METHODS
      5. POISSON–BOLTZMANN THEORY
      6. NUMERICAL SOLUTION OF THE POISSON–BOLTZMANN EQUATION
      7. APPLICATIONS
      8. ACKNOWLEDGMENTS
      9. REFERENCES
    2. 25 PREDICTION OF PROTEIN–NUCLEIC ACID INTERACTIONS
      1. INTRODUCTION
      2. MOTIVATION
      3. POTENTIAL FUNCTIONS FOR PROTEIN–NUCLEIC ACID INTERACTIONS
      4. FLEXIBILITY IN PROTEIN/NUCLEIC ACID COMPLEXES
      5. APPLICATIONS
      6. FUTURE WORK AND CRITICAL CHALLENGES
      7. REFERENCES
    3. 26 PREDICTION OF PROTEIN–PROTEIN INTERACTIONS FROM EVOLUTIONARY INFORMATION
      1. INTRODUCTION
      2. PREDICTION OF INTERACTING REGIONS
      3. PREDICTION OF INTERACTION PARTNERS
      4. FUTURE TRENDS
      5. REFERENCES
    4. 27 DOCKING METHODS, LIGAND DESIGN, AND VALIDATING DATA SETS IN THE STRUCTURAL GENOMICS ERA
      1. INTRODUCTION
      2. DOCKING AND SCORING
      3. DRUG DESIGN IN THE STRUCTURAL PROTEOMICS ERA
      4. SUMMARY
      5. REFERENCES
  11. Section VI STRUCTURE PREDICTION
    1. 28 CASP AND OTHER COMMUNITY-WIDE ASSESSMENTS TO ADVANCE THE FIELD OF STRUCTURE PREDICTION
      1. A MEASURE FOR SUCCESS
      2. COMMUNITY BENCHMARK HISTORY AND FINDINGS
      3. OVERALL PROGRESS
      4. CASP7
      5. WHERE DO WE GO FROM HERE?
      6. ACKNOWLEDGMENT
      7. WEB SITES
      8. REFERENCES
    2. 29 PREDICTION OF PROTEIN STRUCTURE IN 1D: SECONDARY STRUCTURE, MEMBRANE REGIONS, AND SOLVENT ACCESSIBILITY
      1. INTRODUCTION
      2. METHODS
      3. PROGRAMS AND PUBLIC SERVERS
      4. PRACTICAL ASPECTS
      5. EMERGING AND FUTURE DEVELOPMENTS
      6. FURTHER READING
      7. ACKNOWLEDGMENTS
      8. REFERENCES
    3. 30 HOMOLOGY MODELING
      1. INTRODUCTION
      2. STEP 1—TEMPLATE RECOGNITION AND INITIAL ALIGNMENT
      3. STEP 2—ALIGNMENT CORRECTION
      4. STEP 3—BACKBONE GENERATION
      5. STEP 4—LOOP MODELING
      6. STEP 5—SIDE CHAIN MODELING
      7. STEP 6—MODEL OPTIMIZATION
      8. STEP 7—MODEL VALIDATION
      9. STEP 8—ITERATION
      10. ACKNOWLEDGMENTS
      11. REFERENCES
    4. 31 FOLD RECOGNITION METHODS
      1. INTRODUCTION
      2. THEORETICAL BACKGROUND FOR FOLD RECOGNITION
      3. PROTEINS AS SEEN BY A BIOLOGIST
      4. PROTEINS AS SEEN BY A PHYSICIST
      5. SUMMARY
      6. REFERENCES
    5. 32 DE NOVO PROTEIN STRUCTURE PREDICTION: METHODS AND APPLICATION
      1. INTRODUCTION
      2. REDUCED COMPLEXITY MODELS
      3. SCORING FUNCTIONS FOR REDUCED COMPLEXITY MODELS
      4. ROSETTA DE NOVO STRUCTURE PREDICTION
      5. HIGH-RESOLUTION STRUCTURE PREDICTION
      6. CASP: EVALUATION OF STRUCTURE PREDICTIONS
      7. BIOLOGICAL APPLICATIONS OF STRUCTURE PREDICTION
      8. FUTURE DIRECTIONS
      9. REFERENCES
    6. 33 RNA STRUCTURAL BIOINFORMATICS
      1. INTRODUCTION
      2. METHODS FOR PREDICTING SECONDARY STRUCTURES
      3. THREE-DIMENSIONAL MODELING METHODOLOGY
      4. CONCLUSION
      5. WEB RESOURCES
      6. SUGGESTED READINGS
      7. REFERENCES
  12. Section VII THERAPEUTIC DISCOVERY
    1. 34 STRUCTURAL BIOINFORMATICS IN DRUG DISCOVERY
      1. HISTORIC DEVELOPMENT OF DRUG DISCOVERY
      2. MODERN DRUG DISCOVERY
      3. GENERATING PROTEIN STRUCTURES
      4. DRUG TARGETS
      5. LEAD IDENTIFICATION
      6. LEAD OPTIMIZATION
      7. STRUCTURAL BIOINFORMATICS DATABASES
      8. TOWARD PERSONALIZED MEDICINE
      9. CONCLUSION AND FUTURE DIRECTIONS
      10. ACKNOWLEDGMENTS
      11. REFERENCES
      12. FURTHER READING
    2. 35 B-CELL EPITOPE PREDICTION
      1. INTRODUCTION
      2. THE PROBLEM OF B-CELL EPITOPE PREDICTION
      3. ANTIBODY STRUCTURE AND FUNCTION
      4. EXPERIMENTAL METHODS USED FOR B-CELL EPITOPE IDENTIFICATION
      5. HISTORY OF ATTEMPTS AT B-CELL EPITOPE PREDICTION
      6. BIOINFORMATICS METHODS FOR B-CELL EPITOPE PREDICTION
      7. APPLICATIONS
      8. CONCLUSION
      9. ABBREVIATIONS
      10. ACKNOWLEDGMENT
      11. REFERENCES
  13. Section VIII FUTURE CHALLENGES
    1. 36 METHODS TO CLASSIFY AND PREDICT THE STRUCTURE OF MEMBRANE PROTEINS
      1. THE BIOLOGICAL MEMBRANE
      2. THE FOLDING PROCESS OF MEMBRANE PROTEINS
      3. WHY IS IT DIFFICULT TO SOLVE MEMBRANE PROTEIN 3D STRUCTURES?
      4. STRUCTURAL GENOMICS AND MEMBRANE PROTEINS
      5. COMPUTATIONAL METHODS FOR THE IDENTIFICATION OF MEMBRANE PROTEINS AND THE PREDICTION OF THEIR STRUCTURES
      6. WEB-AVAILABLE DATA RESOURCES FOR MEMBRANE PROTEINS
      7. CLASSIFICATION OF MEMBRANE PROTEINS
      8. CONCLUSIONS
      9. REFERENCES
    2. 37 PROTEIN MOTION: SIMULATION
      1. INTRODUCTION
      2. PROTEIN MOTION TIMESCALES, SIZE, AND SIMULATION
      3. COARSE-GRAINED METHODS
      4. CLASSICAL MOLECULAR MECHANICS
      5. QM–MM METHODS
      6. CONCLUSION
      7. ACKNOWLEDGMENTS
      8. REFERENCES
    3. 38 THE SIGNIFICANCE AND IMPACTS OF PROTEIN DISORDER AND CONFORMATIONAL VARIANTS
      1. INTRODUCTION
      2. PROTEIN DISORDER: UNDERSTANDING THE REALM OF “INVISIBLE”
      3. PROTEIN CONFORMATIONAL VARIANTS AND ENSEMBLES
      4. FUTURE DIRECTIONS
      5. REFERENCES
    4. 39 PROTEIN DESIGNABILITY AND ENGINEERING
      1. INTRODUCTION
      2. PROTEIN STRUCTURAL UNIVERSE
      3. DETERMINANTS OF PROTEIN DOMAIN EVOLUTION
      4. MECHANISMS OF PROTEIN DOMAIN EVOLUTION
      5. PROTEIN ALPHABET
      6. LESSONS FOR ENGINEERING STABLE PROTEINS
      7. PROTEIN ENGINEERING: US VERSUS NATURE
      8. CHALLENGES IN PROTEIN DESIGN
      9. CONCLUSIONS
      10. REFERENCES
    5. 40 STRUCTURAL GENOMICS OF PROTEIN SUPERFAMILIES
      1. INTRODUCTION
      2. NYSGXRC
      3. BIOMEDICAL THEME TARGETS: BACKGROUND AND MOTIVATION
      4. BIOMEDICAL THEME TARGETS: SELECTION AND PROGRESS
      5. BIOMEDICAL THEME TARGETS: SELECTED EXAMPLES
      6. PROTEIN TYROSINE PHOSPHATASE (PTPs)
      7. INSULINOMA-ASSOCIATED PROTEIN 2 (IA-2)
      8. SMALL C-TERMINAL DOMAIN PHOSPHATASE 3
      9. CHRONOPHIN
      10. OTHER PHOSPHATASES
      11. BIOMEDICAL THEME TARGETS: POTENTIAL IMPACT ON DRUG DISCOVERY
      12. FRAGMENT CONDENSATION LEAD DISCOVERY STRATEGY APPLIED TO PTP1B
      13. VIRTUAL SCREENING STRATEGY APPLIED TO PP2Cα
      14. BIOMEDICAL THEME TARGETS: CONCLUSION
      15. COMMUNITY-NOMINATED TARGETS: MOTIVATION
      16. COMMUNITY-NOMINATED TARGETS: SELECTION AND PROGRESS
      17. COMMUNITY-NOMINATED TARGETS: FUNCTIONAL CHARACTERIZATION
      18. COMMUNITY-NOMINATED TARGETS: CONCLUSION
      19. OVERALL CONCLUSIONS
      20. ACKNOWLEDGMENTS
      21. REFERENCES
  14. INDEX