Preface to the first edition |
Preface to the second edition |
Preface to the third edition |
Introduction / 1: |
Proteins in their biological context |
The amino acids |
Dogmas-central and peripheral |
The relationship between ammo acid sequence and protein stricture is robust |
Disorder in proteins |
Regulation |
The genetic code |
With life so dependent on proteins, there is ample opportunity for things to go wrong |
Genome sequences |
Gene sequence determines amino acid sequence |
Protein synthesis: the ribosome is the point of contact between genes and proteins-it is the fulcrum of genomics |
Ribosomes were implicated in protein synthesis very early on |
Structural studies of ribosomes by X-ray crystallography and electron microscopy |
Protein stability, denaturation, aggregation, and turnover |
Protein turnover |
Description of protein structures |
Primary structure |
Secondary structure: helices and sheets are favourable conformations of the chain that recur in many proteins |
Tertiary and quaternary structure |
Folding patterns in native proteins-themes and variations |
Modular proteins, and 'mixing and matching' as a mechanism of evolution |
How do proteins develop new functions? |
The study of proteins: in the laboratory, in the cell, in the computer |
Spectroscopic methods of characterizing proteins in solution |
Absorbance and fluorescence of proteins |
Fluorescence is sensitive to the environment and dynamics of the chromophore |
Fluorescence resonance energy transfer (FRET) |
Circular dichroism |
Protein expression patterns in space and time: Proteomics |
Subcellular localization |
The transcriptome |
DNA microaaays |
Mass spectrometry |
Computing in protein science |
Computer-instrument partnerships in the laboratory |
Simulations, including molecular dynamics |
Bioinformatics |
Introduction to databanks for protein science |
Information-retrieval tools |
Web access to the scientific literature |
Useful websites |
Recommended reading |
Exercises and Problems |
Protein structure / 2: |
Structures of the amino acids |
Protein conformation |
Conformational angles and the Sasisekharan-Ramakrishnan-Ramachandran plot |
Sidechain conformation |
Rotamer libraries |
Stabilization of the naïve state |
Conformational change |
Protein folding patterns |
Supersecondary structures |
An album of small structures |
Comparison of the folding patterns of acylphosphatase and a fungal toxin |
Classification of protein structures |
Databanks of protein structure classifications |
SCOP |
SCOP2 |
CATH |
The DALI Database |
A survey of protein structures and functions |
Fibrous proteins |
Enzymes-proteins that catalyse chemical reactions |
Antibodies |
Inhibitors |
Carrier proteins |
Membrane proteins |
Receptors |
Regulatory proteins |
Motor proteins |
Control of protein activity |
Regulation of tyrosine hydroxylase illustrates several control mechanisms common to many proteins |
Control cascades |
Protein structure determination / 3: |
X-ray crystallography |
X-ray structure determination |
X-ray crystallography of proteins |
Interpretation of the electron density: model building and improvement |
The endgame-refinement |
How accurate are the structures? |
X-ray crystallography-the theoretical background |
Nuclear magnetic resonance spectroscopy in structural biology |
NMR spectra of proteins |
Measurement of NMR spectra |
Protein structure determination by NMR |
Assignment of the spectrum |
Transverse relaxation optimized spectroscopy |
From the data to the structure |
Solid-state NMR: magic angle spinning |
Near atomic-resolution low-temperature electron microscopy (cryo-EM) |
Octameric pyruvate-ferredoxin oxidoreductase from Desulfovibrio vulgaris Hildenborough |
Conformational change in activation of human integrin αVβ3 |
Trajectories of conformational change |
The elastic network model accounts for conformational change in Mycobacterium tuberculosis thioredoxin reductase |
The relationship between structure determinations of Isolated proteins, and protein structure and function in vivo |
Protein structure prediction and modeling |
A priori methods of protein structure prediction |
Empirical, or 'knowledge-based', methods of protein structure prediction |
Secondary structure prediction |
Homology modelling |
Fold recognition |
Antibody modeling |
Prediction of special categories of structures |
Conformational energy calculations and molecular dynamics |
ROSETTA |
Protein structure prediction from contact maps derived from correlated mutations in multiple sequence alignments |
Critical Assessment of Structure Prediction (CASP) |
CAPRI |
Bioinformatics of protein sequence and structure / 4: |
Databases and information retrieval |
Amino acid sequence databases |
Protein databases at the U.S. National Center for Biotechnology Information |
Specialized, or 'boutique', databases |
Nucleic acid sequence databases |
Genome databases and genome browsers |
Ensembl |
Expression and proteomics databases |
Debases of macromolecular structure |
Organization of wwPDB entries |
Retrieval of sequences and structures |
Retrieval of amino acid sequences by keyword |
The Protein Information Resource (PIR) and associated databases |
Retrieval of structures by keyword |
Probing databanks with sequence information |
Sequence alignment |
The dotplot |
Dotplots and alignments |
BLAST and PSI-BLAST |
Significance of alignments |
Multiple sequence alignment |
A multiple sequence alignment of thioredoxins shows the importance of conservation patterns |
Analysis of structures |
Superposition of structures |
Structural alignment |
Multiple structure alignment |
Database searching for structures or fragments |
Databases of protein families |
Classifications of protein structures |
Classification and assignment of protein function |
The Enzyme Commission |
The Gene Ontology™ Consortium protein function classification |
The ENZYME database and PROSITE |
Databases of metabolic networks |
Proteins as catalysts: enzyme structure, kinetics, and mechanism / 5: |
What are the crucial features of enzymes? |
Reaction rates and transition states |
The activated complex |
Measurement of reaction rates |
Slow the reaction down |
Fast methods of data collection |
Active sites |
Cofactors |
Protein-ligand binding equilibria |
The Scatchard plot |
Catalysis by enzymes |
Enzyme kinetics |
Derivation of KM and Vmax from rate data |
Measures of effectiveness of enzymes |
Irreversible inhibitor binding |
Multisubstrate reactions |
Enzyme mechanisms |
The mechanism of action of thymidylate synthase |
Computational approaches to enzyme mechanisms |
The mechanism of action of chymotrypsin |
The evidence from kinetics |
The evidence from crystallography |
Blood coagulation |
Thrombosis |
Serpins: serine proteinase inhibitors-conformational disease |
Several conformational states of serpins are known |
Mechanism of proteinase inhibition by serpins |
Evolutionary divergence of enzymes |
The mechanism of action of malate and lactate dehydrogenases |
Enolase, mandelate racemase, and muconate lactonizing enzyme catalyse different reactions but have related mechanisms |
The structure and mechanism of E. coli topoisomerase III |
The sliding filament mechanism of muscle contraction |
ATP synthase |
Membrane transport |
Specificity of the potassium channel from Streptomyces lividans-room to swing a cation? |
Allosteric regulation of protein activity |
The allosteric structural change of haemoglobin |
Proteins with partners / 6: |
General properties of protein-protein interfaces |
Burial of protein surface |
The composition of the interface |
Complementarity |
Specific interactions at protein-protein interfaces |
Phage M13 gene III protein and E. coli TolA |
Multisubunit proteins |
Diseases of protein aggregation |
Amyloidoses |
Alzheimer's disease |
Prion diseases-spongiform encephalopathies |
The immune system |
Antibody structure |
Antibody maturation |
Catalytic antibodies-'abzymes' |
Proteins of the major histocompatibility complex |
T-cell receptors |
Virus structures |
Tomato bushy stunt virus |
Bacteriophage HK97: protein chain-mail |
Photosynthetic reaction centres |
Protein-DNA interactions |
Structural themes in protein-DNA binding and sequence recognition |
Bacteriophage T7 DNA polymerase |
Some protein-DNA complexes that regulate gene transcription |
Evolution of protein structure and function / 7: |
Protein structure classification |
A case study: superpositions and alignments of pairs of proteins with increasingly more-distant relationships |
Structural relationships among homologous domains |
Changes in proteins during evolution give clues to the roles of residues at different positions |
To what constraint are pathways of protein evolution subject? |
Closed β-barrel structures |
The TIM barrel |
Evolution of the globins |
Mammalian globins |
What determines the globin folding pattern? |
Truncated globins |
Expansion of the globin family |
Classification of the globins |
Globin functions |
Phycocyanins and the globins |
Evolution of NAD-binding domains of dehydrogenases |
Comparison of NAD-binding domains of dehydrogenases |
The sequence motif G*G**G |
Structure and evolution of serine proteinases of the chymotrypsin family |
Structures of individual domains |
The domain/domain interface |
The specificity pocket |
The β-barrels in serine proteinase domains and the packing of residues in their interiors |
Evolution of visual pigments and related molecules |
Selection has tuned vertebrate opsins so that the absorption maximum varies with the light environment |
How do proteins evolve new functions? |
Pathways and limits in the divergence of sequence, structure and function |
Evolution of functional change in the enolase superfamily |
Protein evolution at the level of domain assembly |
Domain swapping is a general mechanism for forming an oligomer from a multidomain protein |
Directed evolution |
Directed evolution of subtilisin E |
Enhancement of thermal stability |
Activity in organic solvents |
Affinity selectivity by phage display |
Protein folding and design / 8: |
Why is protein folding so fast? |
Thermodynamics-key concepts |
Entropy |
Spontaneity and equilibrium |
Kinetics |
Thermodynamics, protein folding |
Thermodynamics of mutated proteins |
Experimental character nation of events in protein folding |
The molten globule |
Folding funnels |
The effect of denaturants on rates of folding and unfolding: chevron plots |
The kinetics of folding of mutated proteins gives clues to the structure of the transition state for folding |
Comparison of folding pathways of a natural protein and a circular permutant |
Relationship between native structure and folding |
The hierarchical model of protein folding |
How fast could a protein fold? |
Protein misfolding and the GroEL-GroES chaperone protein |
The GroEL-GroES conformational change |
Protein design |
ab initio design of a hyperstable variant of Streptococcal protein G, β1 domain |
Expanding and contracting the genetic code |
Expansion of the genetic code |
Contraction of the genetic code |
Understanding the contents and layout of the common genetic code |
Proteomics and systems biology / 9: |
Separation and analysis of proteins |
Polyacrylamide gel electrophoresis |
Two-dimensional polyacrylamide gel electrophoresis |
Difference gel electrophoresis |
Identification of components of a complex mixture |
Protein sequencing by mass spectrometry |
Quantitative analysis of relative abundance |
Measuring deuterium exchange in proteins |
'Ome, 'ome, on the range-environmental genomics and proteomics |
Metagenomics |
Metaproteomics |
Dynamic proteomics of the response to cadmium challenge |
Microarrays |
Microarray data are semiquantitative |
Applications of DNA microarrays |
Analysis of microarray data |
Expression patterns in different physiological states |
Expression pattern changes in development: the life cycle of Drosophila melanogaster |
RNAseq |
RNAseq v. microarrays |
Systems biology |
Two parallel networks: physical and logical |
Networks and graphs |
Robustness and redundancy |
Connectivity in networks |
Dynamics, stability, and robustness |
Protein complexes and aggregates |
Protein interaction networks |
Regulatory networks |
Structures of regulatory networks |
Structural biology of regulatory networks |
Gene regulation |
The transcriptional regulatory network of E. coli |
Regulation of the lactose operon in E. coli |
The genetic regulatory network of Saccharomyces cerevisiae |
Adaptability of the yeast regulatory network |
Epilogue |
List of Abbreviations |
Glossary |
Index |