1 Introduction 1.1 Overview of Chemical Biology 1.2 Historical Context and Evolution of Chemical Biology 1.2.1 Biological Effects of Chemicals 1.2.2 Experiment against Vitalism 1.2.3 Manipulating Biomacromolecules 1.2.4 The Development of Synthetic Dyes and Chemotherapy 1.2.5 20th Century and On 1.3 Highlights of Contemporary Work 1.3.1 Bio-orthogonal Chemistry 1.3.2 Directed Evolution 1.3.3 Display Technologies 1.3.4 Deep Learning for Protein Structure Prediction 1.3.5 Chemical Genetics 1.3.6 Unnatural Amino Acids and Bases 1.3.7 Synthetic Genomes Questions References 2 Chemical Principles in Biology 2.1 Basic Chemistry of Biomolecules 2.1.1 The Chemical Composition of Biomolecules 2.1.2 Types of Biomolecules 2.2 Chemical Bonds and Interactions in Biological Systems 2.2.1 Covalent Bonds: The Backbone of Biomolecular Structure 2.2.2 Non-Covalent Interactions and Biomolecular Structure 2.3 Thermodynamics and Kinetics in Biochemical Reactions 2.3.1 Thermodynamics: The Energetics of Biochemical Reactions 2.3.2 Kinetics: The Rate of Biochemical Reactions 2.3.3 The Interplay of Thermodynamics and Kinetics 2.4 Conclusion Questions References 3 The Central Dogma of Molecular Biology 3.1 Discovery 3.2 Genetic Information Flow: Replication，Transcription，Translation 3.2.1 Replication: Preserving Genetic Continuity 3.2.2 Transcription: From DNA to RNA 3.2.3 Translation: Synthesizing Proteins 3.2.4 Integration of Genetic Information Flow 3.3 Exceptions to the Central Dogma of Molecular Biology 3.3.1 Reverse Transcription: RNA to DNA 3.3.2 RNA Replication: RNA to RNA 3.3.3 Perspective on Alternative Information Flow Pathways Questions References 4 Peptide and Protein 4.1 Amino Acid 4.1.1 Chemical Structure and Stereochemistry 4.1.2 Side Chain Groups and Their Properties 4.1.3 Post-Translational Modifications
4.2 Hierarchical Structure of Proteins 4.2.1 Primary Structure and Peptide 4.2.2 Secondary Structure 4.2.3 Tertiary Structure 4.2.4 Quaternary Structure 4.2.5 Protein Structure Determination 4.3 Chemical Synthesis of Peptides 4.3.1 Overview of Solid Phase Peptide Synthesis 4.3.2 Key Steps in Solid Phase Peptide Synthesis 4.3.3 Limitations of Solid Phase Peptide Synthesis 4.4 Native Chemical Ligation 4.5 Expressed Protein Ligation 4.6 Comparison of Biosynthesis and Chemical Synthesis 4.7 Conclusion Questions References 5 Nucleic Acid 5.1 Introduction 5.2 Chemical Composition and Structure of Nucleic Acids 5.3 Biosynthesis of Nucleic Acids 5.3.1 DNA Replication: Mechanism and Enzymatic Machinery 5.3.2 RNA Transcription: Mechanism and Enzymatic Machinery 5.3.3 Coordination and Regulation of Nucleic Acid Biosynthesis 5.4 Polymerase Chain Reaction 5.5 Chemical Synthesis of Nucleic Acids 5.5.1 Principles of Chemical Nucleic Acid Synthesis 5.5.2 Challenges and Advancements in Nucleic Acid Synthesis 5.5.3 Enzymatic synthesis of Nucleic Acids 5.6 Modifications and Labeling of Nucleic Acids 5.6.1 Chemical Modifications of Nucleic Acids 5.6.2 Labeling of Nucleic Acids 5.6.3 Applications of Modified and Labeled Nucleic Acids 5.7 Functional Versatility of Nucleic Acids 5.7.1 Ribozymes: Catalytic RNA Molecules 5.7.2 Riboswitches 5.7.3 Aptamers and DNAzymes: Functional Nucleic Acid Developed in a Lab 5.7.4 DNA as a Material: Structural and Functional Nanotechnology 5.8 Applications of Nucleic Acids 5.8.1 Nucleic Acids as Biosensors 5.8.2 Nucleic Acids for Data Storage 5.8.3 Nucleic Acids in Nanotechnology 5.9 Conclusion Questions References 6 Carbohydrates 6.1 Introduction to Carbohydrates 6.2 Structure and Classification of Carbohydrates 6.2.1 Monosaccharides: Structure and Stereochemistry 6.2.2 Cyclic Structure of Monosaccharides 6.2.3 Monosaccharide Derivatives
6.2.4 Oligosaccharides and Polysaccharides 6.3 Biosynthesis of Carbohydrates 6.3.1 Glycogenesis: Synthesis of Glycogen 6.3.2 Biosynthesis of Complex Carbohydrates: Glycosylation 6.4 Chemical Synthesis of Carbohydrates 6.4.1 Formation of Glycosidic Bonds 6.4.2 Synthesis of Complex Polysaccharides 6.4.3 Automated Chemical Synthesis of Polysaccharides 6.5 Chemical Probes for Carbohydrate Metabolism 6.5.1 Fluorescent Probes for Monitoring Carbohydrate Metabolism 6.5.2 Activity-Based Probes for Profiling Glycosidase and Glycosyltransferase Activities 6.5.3 Inhibitor-Based Probes for Modulating Carbohydrate Metabolism 6.5.4 Probes for Imaging Carbohydrate Metabolism in Vivo 6.6 Conclusion Questions References 7 Metals and Metalloprotein 7.1 Introduction to Metal Ions and Their Biological Importance 7.2 Essential Elements and Trace Metals 7.2.1 Essential Elements 7.2.2 Trace Metals 7.3 Functional Role of Metals in Biology 7.3.1 Role of Metals in Hydrolytic Reactions 7.3.2 Metals in Electron Transfer 7.4 Metal Catalyzed Oxygen Activation 7.4.1 Oxygen Activation by Transition Metals 7.4.2 Biological Implications of Metal-Mediated Oxygen Activation 7.5 Iron and Heme Proteins 7.5.1 Structure and Function of Heme 7.5.2 Oxygen Transport: Hemoglobin and Myoglobin 7.5.3 Electron Transfer: Cytochromes 7.5.4 Catalysis: P450 Monooxygenases 7.6 Conclusion Questions References 8 Bio-orthogonal Reaction 8.1 Definition and Principles 8.2 Bio-orthogonal Reactions 8.2.1 The Staudinger Ligation 8.2.2 Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) 8.2.3 Strain-Promoted Azide-Alkyne Cycloaddition 8.2.4 Tetrazine Ligation 8.2.5 Oxime and Hydrazone Formation 8.2.6 Photoinduced Bio-orthogonal Reactions 8.2.7 Metal-Mediated Bio-orthogonal Reactions 8.3 Applications of Bio-orthogonal Chemistry 8.3.1 Molecular Imaging and Labeling 8.3.2 Drug Delivery and Therapeutics 8.3.3 In Vivo Chemical Biology 8.4 Conclusion
Questions References 9 Orthogonality in Biological Systems 9.1 Semantic and Alphabetic Orthogonality 9.2 Orthogonality in Translation Systems 9.2.1 Orthogonal tRNA and Aminoacyl-tRNA Synthetase Pairs 9.2.2 Orthogonal Ribosomes 9.3 Orthogonal Replication and Transcription System 9.3.1 Orthogonal DNA Replication Systems 9.3.2 Design and Implementation of Orthogonal Transcription Systems 9.4 Genetic Code Expansion 9.4.1 Reassigning Stop Codons 9.4.2 Quadruplet Codon Systems 9.4.3 Genome Redesign 9.4.4 Applications of Unnatural Amino Acids 9.5 Mirror-Image System 9.6 Expansion of the Genetic Alphabet 9.7 Conclusion Questions References 10 Sequencing and Biological Databases 10.1 Nucleic Acid Sequencing and the Omics 10.1.1 Sanger Sequencing: The Foundation of Genomics 10.1.2 The Human Genome Project: A Milestone in Genomic Research 10.1.3 Next-Generation Sequencing: High-Throughput Genomics 10.1.4 The Third-Generation Sequencing: Long Reads for Genomics Study 10.1.5 Metagenomics: Exploring the Microbial World 10.2 Protein Sequencing 10.2.1 Historical Context and Edman Degradation 10.2.2 Mass Spectrometry-Based Protein Sequencing 10.2.3 Nanopore Sequencing of Proteins 10.3 Biological Databases 10.3.1 GenBank: A Comprehensive Nucleotide Sequence Database 10.3.2 UniProt: The Universal Protein Resource 10.3.3 PDB: The Protein Data Bank 10.3.4 KEGG: Kyoto Encyclopedia of Genes and Genomes 10.3.5 BRENDA: The Comprehensive Enzyme Information System 10.3.6 Databases in the AI era Questions References 11 Protein Structure Prediction 11.1 Protein Folding 11.2 Computational Methods for Protein Structure Prediction 11.2.1 Molecular Dynamics Simulations 11.2.2 Homology Modeling and Threading 11.2.3 Rosetta 11.2.4 Critical Assessment of Structure Prediction (CASP) 11.3 AI Methods in Protein Structure Prediction 11.3.1 AlphaFold2: A Landmark Achievement 11.3.2 Protein Language Models and Structure Prediction
11.3.3 Other Structure Prediction Methods and Recent Advances 11.4 Impact of AI-Based Protein Structure Prediction 11.4.1 Establishment of Structural Databases 11.4.2 Transformation from Sequence-Based to Structure-Based Methods 11.5 Conclusion Questions References 12 Molecular Evolution and Directed Evolution 12.1 Natural Evolution 12.1.1 The Principles of Natural Evolution 12.1.2 From Natural to Directed Evolution 12.2 Evolution of Biomacromolecules 12.2.1 Phylogenetic Tree: Tracing Evolutionary Relationships 12.2.2 Information from Molecular Evolution and Rich Sequence Data 12.2.3 Ancestral Sequence Reconstruction 12.2.4 Amino Acid Coevolution 12.2.5 Evolution as a Searching Algorithm 12.3 Directed Evolution: Accelerating Natural Processes 12.3.1 Methods for Introducing Variation 12.3.2 Amplification and Linking of Gene Libraries 12.3.3 Screening and Selection 12.4 AI-Assisted Directed Evolution 12.4.1 Machine Learning in Directed Evolution 12.4.2 Protein Language Models 12.5 In Vivo Directed Evolution 12.5.1 Principles of In Vivo Directed Evolution 12.5.2 Examples of In Vivo Directed Evolution Systems 12.6 Conclusion Questions References 13 Protein Computational Design 13.1 Protein Sequence Space and Fitness Landscape 13.1.1 Exploring the Fitness Landscape 13.1.2 Schemes of Computational Design 13.2 Design Strategies: De Novo vs. Redesign 13.2.1 De Novo Protein Design 13.2.2 Protein Redesign and Mutation 13.2.3 Biochemical and Structural Biology Knowledge in Protein Design 13.3 Protein Design: An Overview 13.3.1 Historical Context 13.3.2 Peptide Design 13.3.3 Rosetta in Protein Design 13.4 Deep Learning-Based Methods in Computational Protein Design 13.4.1 The Inverse Folding Problem and Sequence Design 13.4.2 Backbone Design 13.4.3 Sequence-Structure Co-Design 13.4.4 Strategies toward Designing Function 13.5 Conclusion 13.5.1 Interplay of Experiment and Computation 13.5.2 Database for Training
13.5.3 Integration with Directed Evolution 13.5.4 Multimodal Design Questions References 14 Chemical Genetics 14.1 Classical Genetics 14.1.1 Forward Genetics 14.1.2 Reverse Genetics 14.2 Protein-Small Molecule Interactions 14.3 Principles of Chemical Genetics 14.3.1 Forward Chemical Genetics 14.3.2 Reverse Chemical Genetics 14.3.3 Methodologies in Chemical Genetics 14.4 Chemical Genetics in Drug Discovery Questions References 15 Biocatalysis 15.1 Chemo-enzymatic Catalysis 15.2 Artificial Enzymes 15.3 Photocatalysis 15.3.1 Strategies for Combining Biocatalysis and Photocatalysis 15.3.2 Repurposing Natural Photoenzymes 15.3.3 Elucidating New Photoreactivity Within Cofactor-Dependent Enzymes 15.3.4 Synergistic Combination of External Photocatalysis and Enzymes 15.3.5 Construction of Artificial Photoenzymes 15.4 Biocatalysis with Functional Materials 15.5 Conclusion Questions References 16 Biopharmaceuticals 16.1 Introduction to Biopharmaceuticals 16.2 Categories of Biopharmaceuticals 16.2.1 Biocatalysis and Biotransformation Products 16.2.2 Biomacromolecules 16.2.3 Cells and Cell Components 16.3 Case Studies in Biopharmaceuticals 16.3.1 Insulin as a Pioneering Biopharmaceutical 16.3.2 Biocatalysis in the Synthesis of Sitagliptin 16.3.3 Monoclonal Antibodies Engineering 16.3.4 CAR-T Therapy: A New Frontier in Cancer Treatment 16.4 Conclusion Questions References
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