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CHAPTER 1 INTRODUCTION1

1.1 Prelude1

1.2 Covalent Bonds4

1.3 Noncovalent Interactions5

1.3.1 Electrostatic Interaction6

1.3.2 Van der Waals Interaction6

1.3.3 Hydrogen Bond6

1.3.4 Hydrophobic Interaction7

1.3.5 Steric Repulsion8

1.4 Isomerism：Configuration versus Conformation8

1.5 Trilogy11

1.6 References13

CHAPTER 2 MONOMER CONSTITUENTS OF BIOMACROMOLECULES15

2.1 Nucleotides：Constituents of Nucleic Acids15

2.2 α-Amino Acids：Constituents of Proteins18

2.3 Monosaccharides：Constituents of Glycans23

2.4 Addendum28

2.5 References30

CHAPTER 3 PURIFICATION AND CHARACTERIZATION31

3.1 Purification：OvervieW31

3.2 Purification：Chromatography34

3.3 Purification：Electrophoresis40

3.4 Characterization：General44

3.4.1 Purity44

3.4.2 Molecular Weight44

3.4.3 Molecular Dimension50

3.5 Characterization：Specific51

3.5.1 Melting Temperature of DNA51

3.5.2 Buoyant Density of Biomacromolecules52

3.5.3 Isoelectric pH of Proteins52

3.5.4 Removal of Glycosides from Glycoproteins53

3.6 References53

CHAPTER 4 BIOMACROMOLECULAR STRUCTURE：NUCLEIC ACIDS55

4.1 Structural Organization55

4.1.1 Structural Hierarchy55

4.1.2 Representation of Structures of Nucleic Acids56

4.2 Sequence Analysis of Nucleic Acids57

4.2.1 General57

4.2.2 Chemical Cleavage Method59

4.2.3 Enzymatic Chain Term in ation/Dideoxy Method60

4.2.4 Mass Spectrometric Analysis61

4.2.5 Automated DNA Sequencing Technology62

4.3 Secondary Structure and Structure Polymorphism of DNA63

4.3.1 Key Structural Features of Nucleic Acids63

4.3.2 DNA Polymorphism66

4.3.3 Alternative Structures of DNA69

4.4 Supercoiling and Tertiary Structure of DNA77

4.4.1 DNA Topoisomers77

4.4.2 Superhelical Density and Energetics of Supercoiling.80

4.5 Classification and Structures of RNA81

4.5.1 Structures of RNA81

4.5.2 Transfer RNA82

4.5.3 Ribosomal RNA83

4.5.4 Messenger RNA84

4.5.5 Other Classes of RNA85

4.6 RNA Folds and Structure Motifs86

4.6.1 RNA Folds86

4.6.2 Structure Motifs of RNA86

4.7 Energetics of Nucleic Acid Structure89

4.8 Nucleic Acid Application90

4.9 References91

CHAPTER 5 BIOMACROMOLECULAR STRUCTURE：PROTEINS94

5.1 Architecture of Protein Molecules94

5.1.1 Introduction94

5.1.2 Representation of Protein Structures94

5.2 Primary Structure of Proteins：Chemical and Enzymatic Sequence Analysis95

5.2.1 Amino Acid Composition96

5.2.2 Peptide Cleavage，Separation and Analysis97

5.2.3 Terminal and Sequence Determination97

5.2.4 Peptide Ladder Sequencing101

5.3 Primary Structure of Proteins：Sequence Analysis by Tandem Mass Spectrometry101

5.3.1 An Application of Mass Spectrometry（MS）in Protein Chemistry101

5.3.2 Application of Tandem Mass Spectrometry（MS-MS）in Protein Sequence Analysis103

5.4 Conformational Map108

5.5 Secondary Structures and Motifs of Proteins110

5.5.1 α-Helical Structure111

5.5.2 β-Sheet Structure113

5.5.3 Nonrepetitive Structure：Connection （Loop）and Turn115

5.5.4 Notes to Secondary Structures of Globular Proteins116

5.5.5 Motifs：Supersecondary Structures117

5.6 Domains and Tertiary Structures of Proteins118

5.6.1 Domain Structures119

5.6.2 Tertiary Structures and Protein Folds121

5.6.3 Folds and Protein Binding126

5.6.4 Membrane Proteins128

5.6.5 Fibrous Proteins128

5.6.6 Circular（Cyclic）Proteins129

5.6.7 Representation of Protein Topology130

5.6.8 Accessible Surface of Folded Structures130

5.7 Classification of Protein Structures133

5.7.1 α-Helical Proteins133

5.7.2 β-Sheet Proteins133

5.7.3 α＋β Proteins135

5.7.4 α/β Proteins135

5.7.5 Multidomain Structures135

5.7.6 Membrane and Cell Surface Proteins136

5.7.7 Irregular and Small Proteins136

5.8 Quaternary（Subunit）Structures of Proteins137

5.9 Quinteryary Structure Exemplified：Nucleoproteins140

5.9.1 Chromosomes140

5.9.2 Ribosomes141

5.9.3 Spliceosome and Splicing Activities142

5.10 Conformational Energetics143

5.11 References144

CHAPTER 6 BIOMACROMOLECULAR STRUCTURE：POLYSACCHARIDES147

6.1 Propagation of Polysaccharide Chains147

6.1.1 Introduction147

6.1.2 Representation of Glycan Structures148

6.1.3 Toward Linear Code for Glycans148

6.2 Sequence Analysis of Polysaccharides：Primary Structure153

6.2.1 Hydrolysis to Constituent Monosaccharides154

6.2.2 Chemical Methods154

6.2.3 Enzymatic Methods155

6.2.4 Spectrometric Methods157

6.3 Conformation：Secondary and Tertiary Structures of Polysaccharide Chains161

6.4 Conformation：Description of Some Polysaccharide Structures163

6.4.1 Starch163

6.4.2 Glycogen164

6.4.3 Pectins165

6.4.4 Cellulose165

6.4.5 Chitin166

6.5 Glycobiology：Study of Glycoprotein-Associated Glycans167

6.5.1 Glycoprotein and Glycoforms167

6.5.2 Structure Diversity of Oligosaccharide Chains168

6.5.3 Structural Analysis174

6.6 Neoglycoproteins177

6.7 Organizational Levels of Biomacromolecular Structures177

6.8 References181

CHAPTER 7 STUDIES OF BIOMACROMOLECULAR STRUCTURES：SPECTROSCOPIC ANALYSIS OF CONFORMATION183

7.1 Biochemical Spectroscopy：Overview183

7.2 Ultraviolet and Visible Absorption Spectroscopy185

7.2.1 Basic Principles185

7.2.2 Amino Acid Residues and Peptide Bonds187

7.2.3 Purines，Pyrimidines and Nucleic Acids188

7.2.4 Perturbation Difference Absorption Spectroscopy189

7.3 Fluorescence Spectroscopy190

7.4 Infrared Spectroscopy193

7.4.1 Basic Principles193

7.4.2 Biochemical Applications195

7.5 Nuclear Magnetic Resonance Spectroscopy197

7.5.1 Basic Principles197

7.5.2 Two-Dimensional Fourier Transform NMR202

7.5.3 NMR of Proteins203

7.5.4 NMR of Nucleic Acids206

7.5.5 NMR of Glycans207

7.6 Optical Rotatory Dispersion and Circular Dichroism Spectroscopy208

7.6.1 Basic Principles208

7.6.2 ORD/CD Spectra and Protein Secondary Structures209

7.6.3 Empirical Applications of ORD and CD212

7.7 X-ray Diffraction Spectroscopy214

7.7.1 Basic Principles214

7.7.2 Crystallographic Study of Biomacromolecules216

7.8 References219

CHAPTER 8 STUDIES OF BIOMACROMOLECULAR STRUCTURES：CHEMICAL SYNTHESIS220

8.1 Rationale220

8.2 Synthetic Strategy：Conventional Approach220

8.2.1 Protection and Deprotection of Common Functional Groups221

8.2.2 Protection and Deprotection Specific to Peptide Synthesis223

8.2.3 Coupling Reaction225

8.3 Synthetic Strategy：Solid Phase Approach225

8.3.1 General Concept225

8.3.2 Solid-Phase Polymer Support230

8.4 Practice of Solid Phase Synthesis and Its Application232

8.4.1 Oligo- and Polypeptide Synthesis232

8.4.2 Oligo- and Polynucleotide Synthesis236

8.4.3 Oligo- and Polysaccharide Synthesis237

8.5 Combinatorial Synthesis241

8.5.1 Parallel Synthesis241

8.5.2 Mixture Synthesis242

8.6 Biochemical Polypeptide Chain Ligation245

8.7 References247

CHAPTER 9 STUDIES OF BIOMACROMOLECULAR STRUCTURES：COMPUTATION AND MODELING249

9.1 Potential Energy and Molecular Thermodynamics249

9.2 Molecular Modeling：Molecular Mechanical Approach252

9.2.1 Introduction252

9.2.2 Energy Calculation254

9.2.3 Energy Minimization256

9.2.4 Molecular Dynamics258

9.2.5 Conformational Search261

9.2.6 Remaining Issues262

9.2.7 Computational Application of Molecular Modeling Packages263

9.3 Statistical Thermodynamics264

9.3.1 General Principles264

9.3.2 Transitions of Regular Structures：Two-State Models268

9.3.3 Random Structure：Random-Walk Problem271

9.4 Structural Transition：Examples273

9.4.1 Coil-Helix Transition in Polypeptides273

9.4.2 Helical Transition in Nucleic Acids274

9.4.3 Topological Transition of Closed Circular DNA Duplex276

9.5 Structure Prediction from Sequence by Statistical Methods276

9.5.1 Approaches276

9.5.2 Secondary Structure of Proteins and Beyond277

9.5.3 Functional Sites of Proteins280

9.5.4 Nucleic Acid Fold281

9.6 Molecular Docking：Prediction of Biomacromolecular Binding282

9.7 References286

CHAPTER 10 BIOMACROMOLECULAR INTERACTION289

10.1 Biomacromolecules in Solution289

10.2 Multiple Equilibria291

10.2.1 Single-Site Binding291

10.2.2 Multiple-Site Binding：General292

10.2.3 Multiple-Site Binding：Equivalent Sites293

10.2.4 Multiple-Site Binding：Nonequivalent Sites294

10.3 Allosterism and Cooperativity295

10.3.1 Models295

10.3.2 Diagnostic Tests for Cooperativity299

10.4 Specificity and Diversity of Antibody-Antigen Interactions300

10.4.1 Structure of Antibody300

10.4.2 Antibody-Antigen Complex303

10.5 Complementarity in Nucleic Acid Interactions305

10.5.1 DNA-Protein Interaction305

10.5.2 Binding of Intercalation Agent to Supercoiled DNA309

10.5.3 RNA-Protein Interaction310

10.6 Molecular Recognition in Carbohydrate-Lectin Interaction312

10.6.1 Classification and Structures of Lectins312

10.6.2 Lectin-Carbohydrate Recognition：General315

10.6.3 Lectin-Carbohydrate Recognition：Ligand Discrimination318

10.7 References320

CHAPTER 11 BIOMACROMOLECULAR CATALYSIS322

11.1 Biocatalyst：Definition and Classification322

11.2 Characteristics of Enzymes325

11.2.1 Enzymes：Catalytic Proteins325

11.2.2 Catalytic Efficiency326

11.2.3 Enzyme Specificity328

11.2.4 Active Site of Enzyme330

11.2.5 Multienzyme Complex and Multifunctional Enzymes331

11.3 Enzyme Kinetics333

11.3.1 Fundamental of Enzyme Kinetics333

11.3.2 Steady-State Kinetic Treatment of Enzyme Catalysis336

11.3.3 Quasi-Equilibrium Treatment of Random Reactions338

11.3.4 Cleland’s Approach339

11.3.5 Nonlinear Kinetics339

11.3.6 Environmental Effects341

11.4 Enzyme Mechanisms344

11.4.1 Essay on Enzyme Reaction Mechanism344

11.4.2 Studies of Enzyme Mechanism：Active Site349

11.4.3 Studies of Enzyme Mechanism：Transition State356

11.4.4 Structure-Activity Relationship357

11.4.5 X-ray Crystallographic Studies and Refinement361

11.4.6 Case Studies of Enzyme Mechanisms361

11.5 Enzyme Regulation374

11.5.1 Elements of Enzyme Regulation374

11.5.2 Covalent Modifications of Enzymes and Cascade Effect374

11.5.3 Control of Enzyme Catalytic Activity by Effectors377

11.5.4 Structure Basis of Allosteric Regulation：Glycogen Phosphorylase381

11.6 Abzyme383

11.7 Ribozyme386

11.7.1 Characteristics of Catalytic RNA386

11.7.2 Description of Ribozymes388

11.7.3 Strategies for Ribozyme Catalysis392

11.8 References394

CHAPTER 12 SIGNAL TRANSDUCTION AND BIODEGRADATION398

12.1 Chemical Transduction：Metabolism398

12.2 Elements of Signal Transduction400

12.2.1 First Messengers400

12.2.2 Receptors400

12.2.3 Second Messengers403

12.2.4 Transducers：GTP-Binding Proteins403

12.3 Effector Enzymes and Signal Transduction406

12.3.1 Adenylyl Cyclase and Signal Transduction406

12.3.2 Phospholipase C and Signal Transduction408

12.4 Topics on Signal Transduction410

12.4.1 Calcium Signaling410

12.4.2 Phosphorylation and Dephosphorylation in Signaling414

12.4.3 Signal Pathways Operated by Receptor Protein Tyrosine Kinase417

12.4.4 Signaling Pathways Operated by Nonreceptor Proteins Tyrosine Kinase419

12.5 Apoptosis419

12.6 Hydrolysis versus Phosphorolysis of Glycans422

12.7 Nucleolysis of Nucleic Acids424

12.8 Proteolysis and Protein Degradation426

12.8.1 Proteolytic Mechanism426

12.8.2 Protein Degradation Pathway427

12.9 References433

CHAPTER 13 BIOSYNTHESIS AND GENETIC TRANSMISSION436

13.1 Saccharide Biosynthesis and Glycobiology436

13.1.1 Biosynthesis of Biopolymer：Distributive versus Processive436

13.1.2 Biosynthesis of oligo- and poly-saccharide chains436

13.1.3 Biosynthesis of Glycoproteins437

13.2 Genetic Information and Transmission442

13.3 DNA Replication and Repair445

13.3.1 DNA Replication：Overview445

13.3.2 DNA Replication：Enzymology448

13.3.3 Reverse Transcription455

13.3.4 Post-Replicational Modification456

13.3.5 DNA Repair458

13.4 Biosynthesis and Transcription of RNA461

13.4.1 RNA Transcription：Prokaryotic System461

13.4.2 RNA Transcription：Eukaryotic System463

13.4.3 Regulation of RNA Transcription466

13.4.4 Posttranscriptional Processing/Modification469

13.5 Translation and Protein Biosynthesis472

13.5.1 Protein Translation：Overview472

13.5.2 Protein Translation：Processes475

13.5.3 Decoding Mechanism479

13.5.4 Recoding，Frameshifting and Expanded Genetic Code481

13.5.5 Rescue System for Stalled Ribosomes483

13.5.6 Posttranslational Modifications of Protein484

13.5.7 Protein Translocation488

13.6 Folding of Biomacromolecules491

13.6.1 Overview491

13.6.2 RNA Folding491

13.6.3 In vitro Protein Folding Pathway492

13.6.4 Molecular Chaperone in Cytosolic Protein Folding494

13.7 Bioengineering of Biomacromolecules494

13.7.1 Recombinant DNA Technology494

13.7.2 RNA Engineering500

13.7.3 Protein Engineering501

13.7.4 Antibody Engineering506

13.8 References511

CHAPTER 14 BIOMACROMOLECULAR INFORMATICS515

14.1 Overview515

14.2 Biosequences515

14.2.1 Sequencing Biomacromolecules515

14.2.2 Sequence Similarity and Pair-Wise Alignment517

14.2.3 Similarity Search and Multiple Sequence Alignment522

14.2.4 Statistical Significance of Sequence Search/Alignments524

14.3 Microarray：General Description525

14.3.1 Introduction525

14.3.2 Surface Preparation for Microarray525

14.3.3 Microarray Targets528

14.3.4 Microarray Probes529

14.3.5 Biochemical Reaction of Microarray530

14.3.6 Microarray Detection530

14.3.7 Data analysis in microarray531

14.4 Computer Technology533

14.4.1 Machine：Computer533

14.4.2 Tool：Program，Language and Programming535

14.4.3 Molecular Graphics537

14.4.4 Resource：Internet540

14.3.5 Internet Resources of Biochemical Interest546

14.5 Informatics548

14.5.1 Introduction to Database548

14.5.2 Biochemical Databases549

14.5.3 Database Retrieval551

14.6 Gene Ontology553

14.7 References555

CHAPTER 15 GENOMICS558

15.1 Genome：Features and Organization558

15.1.1 Genome Features558

15.1.2 Gene Mapping561

15.1.3 Information Content of Nucleotide Sequence563

15.1.4 DNA Library564

15.1.5 Alternative Splicing566

15.1.6 Gene Variation：Single Nucleotide Polymorphism567

15.2 Genome Informatics：Databases and Web Servers568

15.2.1 Nucleic Acid Databases568

15.2.2 Nucleic Acid Analysis Servers571

15.3 Approaches to Gene Identification571

15.3.1 Masking Repetitive DNA575

15.3.2 Database Searches576

15.3.3 Codon Bias Detection576

15.3.4 Detecting Functional Sites in the DNA577

15.4 Gene Expression578

15.4.1 Expression Profiling：DNA Chips578

15.4.2 Gene Expression：mRNA Quantification and Transcriptome Analysis583

15.5 Genome Project587

15.6 References590

CHAPTER 16 PROTEOMICS594

16.1 Proteome：Features and Properties594

16.1.1 Proteome Features594

16.1.2 Protein Identity Based on Composition and Properties595

16.1.3 Physicochemical Properties Based on Sequence596

16.2 Proteome Informatics：Sequence Databases and Servers598

16.2.1 Amino Acid Sequence598

16.2.2 Primary Sequence Database599

16.2.3 Secondary Sequence Database602

16.2.4 Boutique Databases605

16.3 Proteome Informatics：Structure Databases and Servers605

16.3.1 Structure Database：Primary Archive605

16.3.2 Structure Databases：Substructures and Structure Classification608

16.4 Proteome Informatics：Proteomic Servers610

16.4.1 Proteome Analysis and Annotation610

16.4.2 Integrated Databases613

16.4.3 Post-Translational Modifications and Functional Sites614

16.5 Protein Structure Analysis Using Bioinformatics616

16.5.1 Secondary Structure Predictions617

16.5.2 Three-Dimensional Structure Modeling618

16.5.3 Sequence Similarity and Alignment619

16.5.4 Structure Similarity and Overlap620

16.5.5 Fold Recognition and Threading623

16.5.6 Homology Modeling623

16.5.7 Ab initio Prediction of Protein Structure624

16.5.8 Solvation625

16.5.9 On-line Protein Structure Prediction626

16.5.10 Protein-Protein Interaction628

16.6 Investigation of Proteome Expression and Function629

16.6.1 Two-Dimensional Gel Electrophoresis629

16.6.2 Proteome Analysis by Mass Spectrometry631

16.6.3 Analysis of Posttranslational Modification by Mass Spectrometry634

16.6.4 High Throughput Protein Crystallography635

16.6.5 Protein-Protein Interactions by Two-Hybrid Assay636

16.6.6 Protein Chip638

16.6.7 Activity-Based Probe640

16.6.8 Nonsense Suppression Mutagenesis643

16.7 Metabolome647

16.8 References650

CHAPTER 17 GLYCOMICS655

17.1 Features of Glycomics655

17.1.1 Glycobiology：Nomenclature and Representation of Glycans655

17.1.2 Glycobiology：Glycoforms657

17.1.3 Glycomics：Response to Post-Genomic Era659

17.2 Glycomic Databases and Servers661

17.2.1 Glycan Structure661

17.2.2 Glycan Analysis663

17.2.3 Glycosylation of Proteins665

17.3 Glycomics：Genetic Approaches666

17.4 Glycomics：Proteoglycomic Approaches668

17.4.1 Characterization of Glycosylation Sites668

17.4.2 Lectin and Glycoenzyme-Based Proteoglycomics670

17.4.3 Metabolic Oligosaccharide Engineering672

17.4.4 Recombinant Glycoproteins673

17.5 Glycomics：Chemoglycomic Approaches674

17.5.1 Structural Analysis of Glycans674

17.5.2 Glycoprotein Syntheses in Glycomics674

17.5.3 Glycochip675

17.6 References678

CHAPTER 18 BIOMACROMOLECULAR EVOLUTION680

18.1 Variation in Biomacromolecular Sequences680

18.1.1 Mutation as Driving Force of Evolution680

18.1.2 Evolutionary Rate and Role of Selection682

18.2 Element of Molecular Phylogeny685

18.3 Phylogenetic Analysis of Biosequences687

18.3.1 General Consideration687

18.3.2 Sequence Data687

18.3.3 Phylogenetic Method：Distance-Based Approaches690

18.3.4 Phylogenetic Method：Character-Based Approaches691

18.3.5 Construction of Phylogenetic Tree692

18.3.6 Assessment692

18.4 Application of Sequence Analyses in Phylogenetic Inference693

18.4.1 Phylogenetic Analysis Software693

18.4.2 Phylogenetic Analysis with PHYLIP693

18.4.3 Phylogenetic Analysis Online697

18.5 Evolution of Biosequences697

18.5.1 Evolution of Nucleic Acid Sequence697

18.5.2 Regulation of Evolutionary Change699

18.6 Evolution of Protein Structure and Function701

18.6.1 Evolution of Protein Complexity：General702

18.6.2 Evolution of Protein Complexity：Domain Duplication703

18.6.3 Evolution of Protein Structure：Fold Change704

18.6.4 Evolution of Protein Function：Catalytic Site Convergence versus Divergence706

18.7 References708

INDEX710