前言
化学生物学是一门跨学科的研究领域，它结合了化学和生物学的方法和原理，旨在深入理解生物系统的化学基础，并利用化学工具和技术来解析、操控和模拟生物过程。该领域的研究正在改变我们对生物过程的理解，从而导致医学、生物技术和环境科学领域的突破性发现。近年来的诺贝尔化学奖，包括2018 年的定向进化和表面展示、2022 年的生物正交化学和点击反应、2024 年的蛋白质结构预测和计算设计均为化学生物学及相关领域的研究。
北京理工大学化学生物学全英文课程2019 年来面向生物化工、制药工程、药学等相关专业国内研究生和留学生开设，并有同名课程上线。在教学过程中，介绍生物分子的基础知识，化学生物学的原理和技术，同时兼顾介绍学科历史和国内外前沿进展，在双语教学中，我们形成了英文版教材Introduction to Chemical Biology。编写过程中，我们充分考虑到学生的学习理解能力，力求做到循序渐进、由浅入深和通俗易懂。书中部分内容来自编者的科研论文，同时参考了相关英文原版教材与英文科技文献，在形成讲义后，又经过多年课堂实践、几经易稿而成。
本教材的主要内容包括化学生物学的基本概念、原理方法和应用。全书共16 章，分为三个部分，从基础知识逐步深入到前沿领域。第一部分(第1~6 章)介绍生物分子的结构、功能和化学合成，同时简述了支配生物系统的基本化学原理。第二部分(第7~14 章)介绍化学生物学的原理和技术，包括生物系统中正交性的工程设计、序列-结构-功能关系的探索， 以及小分子-蛋白质相互作用的研究。第三部分(第15~16 章)转向应用，展示化学生物学如何推动生物催化和生物制药的进步， 为可持续化学和变革性治疗开辟新的可能性。
本书的编写分工如下：1~6 章由姜雨佳编写，7~9、14~16 章由袁飞燕编写，10~13章由于洋编写，全书由于洋汇总定稿。
最后，感谢化学工业出版社编辑给予的大力帮助。由于编者水平有限，疏漏和不当之处在所难免，谨请读者批评指正。
主编
2026年1月
Preface
Chemical biology is an interdisciplinary research field that combines methods and principles from chemistry and biology to gain a deep understanding of the chemical basis of biological systems and to utilize chemical tools and techniques to analyze，manipulate，and simulate biological processes. Research in this field is transforming our understanding of biological processes， leading to groundbreaking discoveries in medicine，biotechnology，and environmental science. Recent Nobel Prizes in Chemistry，including those awarded in 2018 for directed evolution and surface display，2022 for bioorthogonal chemistry and click reactions，and 2024 for protein structure prediction and computational design highlight research in chemical biology and related fields.
Beijing Institute of Technologys Chemical Biology course，offered in English since 2019，is open to both domestic and international graduate students in biochemical engineering，pharmaceutical engineering，and pharmacy. A similar course is also available as massive open
online course. The course introduces the fundamentals of biomolecules， the principles and techniques of chemical biology，and the history of the discipline as well as cutting-edge advances both domestically and internationally. The English textbook，Introduction to Chemical Biology，
was developed with students?? learning and comprehension abilities in mind，striving for a step-bystep，progressive，and accessible approach. Part of the contents in this book is derived from the authors?? research papers，while also referencing relevant English original textbooks and literature. After the lecture notes were developed，they were further refined through years of classroom practice and several revisions.
This textbook provides a gateway into the field of chemical biology，exploring how chemistry and biology intersect to reveal the principles of life and enable new technologies. Across 16 chapters，the book is organized into three parts that move from foundations to frontiers. Part Ⅰ (chapter 1~6) lays the groundwork by introducing biomoleculestheir structures，functions，and chemical synthesiswhile highlighting the fundamental chemical principles that govern biological systems. Part Ⅱ (chapter 7~14) introduces the principles and techniques of chemical biology，including the engineering of orthogonality in biological systems， the exploration of sequence-structurefunction relationships，and the study of small molecule-protein interactions. Part Ⅲ ( Chapter 15~16) turns to applications，demonstrating how chemical biology drives advances in biocatalysis and biopharmaceuticals， opening possibilities for sustainable chemistry and transformative therapies.
The writing of this book is divided into the following sections：Yujia Jiang for Chapters 1~6; Feiyan Yuan for Chapters 7~9 and 14~16; and Yang Yu for Chapters 10~13，with the entire book finalized by Yang Yu.
Finally，we would like to express our gratitude to the editor from Chemical Industry Press，for their strong support.
Due to the limited expertise of the authors，errors are inevitable，and we welcome constructive criticism and corrections.
Editor-in-Chief
January 2026
1 Introduction 001
1.1 Overview of Chemical Biology 002
1.2 Historical Context and Evolution of Chemical Biology 002
1.2.1 Biological Effects of Chemicals 003
1.2.2 Experiment against Vitalism 004
1.2.3 Manipulating Biomacromolecules 004
1.2.4 The Development of Synthetic Dyes and Chemotherapy 005
1.2.5 20th Century and On 006
1.3 Highlights of Contemporary Work 006
1.3.1 Bio-orthogonal Chemistry 007
1.3.2 Directed Evolution 007
1.3.3 Display Technologies 007
1.3.4 Deep Learning for Protein Structure Prediction 007
1.3.5 Chemical Genetics 008
1.3.6 Unnatural Amino Acids and Bases 008
1.3.7 Synthetic Genomes 008
Questions 009
References 009
2 Chemical Principles in Biology 010
2.1 Basic Chemistry of Biomolecules 011
2.1.1 The Chemical Composition of Biomolecules 011
2.1.2 Types of Biomolecules 011
2.2 Chemical Bonds and Interactions in Biological Systems 013
2.2.1 Covalent Bonds：The Backbone of Biomolecular Structure 013
2.2.2 Non-Covalent Interactions and Biomolecular Structure 014
2.3 Thermodynamics and Kinetics in Biochemical Reactions 017
2.3.1 Thermodynamics：The Energetics of Biochemical Reactions 017
2.3.2 Kinetics：The Rate of Biochemical Reactions 018
2.3.3 The Interplay of Thermodynamics and Kinetics 019
2.4 Conclusion 019
Questions 020
References 020
3 The Central Dogma of Molecular Biology 021
3.1 Discovery 022
3.2 Genetic Information Flow：Replication，Transcription，Translation 024
3.2.1 Replication：Preserving Genetic Continuity 024
3.2.2 Transcription：From DNA to RNA 025
3.2.3 Translation：Synthesizing Proteins 025
3.2.4 Integration of Genetic Information Flow 026
3.3 Exceptions to the Central Dogma of Molecular Biology 027
3.3.1 Reverse Transcription：RNA to DNA 027
3.3.2 RNA Replication：RNA to RNA 028
3.3.3 Perspective on Alternative Information Flow Pathways 028
Questions 029
References 030
4 Peptide and Protein 031
4.1 Amino Acid 032
4.1.1 Chemical Structure and Stereochemistry 032
4.1.2 Side Chain Groups and Their Properties 033
4.1.3 Post-Translational Modifications 034
4.2 Hierarchical Structure of Proteins 035
4.2.1 Primary Structure and Peptide 035
4.2.2 Secondary Structure 038
4.2.3 Tertiary Structure 040
4.2.4 Quaternary Structure 042
4.2.5 Protein Structure Determination 044
4.3 Chemical Synthesis of Peptides 047
4.3.1 Overview of Solid Phase Peptide Synthesis 047
4.3.2 Key Steps in Solid Phase Peptide Synthesis 047
4.3.3 Limitations of Solid Phase Peptide Synthesis 049
4.4 Native Chemical Ligation 050
4.5 Expressed Protein Ligation 053
4.6 Comparison of Biosynthesis and Chemical Synthesis 056
4.7 Conclusion 057
Questions 058
References 059
5 Nucleic Acid 060
5.1 Introduction 061
5.2 Chemical Composition and Structure of Nucleic Acids 062
5.3 Biosynthesis of Nucleic Acids 065
5.3.1 DNA Replication：Mechanism and Enzymatic Machinery 065
5.3.2 RNA Transcription：Mechanism and Enzymatic Machinery 066
5.3.3 Coordination and Regulation of Nucleic Acid Biosynthesis 067
5.4 Polymerase Chain Reaction 067
5.5 Chemical Synthesis of Nucleic Acids 070
5.5.1 Principles of Chemical Nucleic Acid Synthesis 070
5.5.2 Challenges and Advancements in Nucleic Acid Synthesis 072
5.5.3 Enzymatic synthesis of Nucleic Acids 072
5.6 Modifications and Labeling of Nucleic Acids 075
5.6.1 Chemical Modifications of Nucleic Acids 075
5.6.2 Labeling of Nucleic Acids 075
5.6.3 Applications of Modified and Labeled Nucleic Acids 076
5.7 Functional Versatility of Nucleic Acids 077
5.7.1 Ribozymes：Catalytic RNA Molecules 077
5.7.2 Riboswitches 078
5.7.3 Aptamers and DNAzymes：Functional Nucleic Acid Developed in a Lab 078
5.7.4 DNA as a Material：Structural and Functional Nanotechnology 080
5.8 Applications of Nucleic Acids 080
5.8.1 Nucleic Acids as Biosensors 080
5.8.2 Nucleic Acids for Data Storage 081
5.8.3 Nucleic Acids in Nanotechnology 083
5.9 Conclusion 084
Questions 085
References 085
6 Carbohydrates 086
6.1 Introduction to Carbohydrates 087
6.2 Structure and Classification of Carbohydrates 088
6.2.1 Monosaccharides：Structure and Stereochemistry 088
6.2.2 Cyclic Structure of Monosaccharides 089
6.2.3 Monosaccharide Derivatives 091
6.2.4 Oligosaccharides and Polysaccharides 091
6.3 Biosynthesis of Carbohydrates 092
6.3.1 Glycogenesis：Synthesis of Glycogen 092
6.3.2 Biosynthesis of Complex Carbohydrates：Glycosylation 094
6.4 Chemical Synthesis of Carbohydrates 094
6.4.1 Formation of Glycosidic Bonds 094
6.4.2 Synthesis of Complex Polysaccharides 098
6.4.3 Automated Chemical Synthesis of Polysaccharides 098
6.5 Chemical Probes for Carbohydrate Metabolism 099
6.5.1 Fluorescent Probes for Monitoring Carbohydrate Metabolism 100
6.5.2 Activity-Based Probes for Profiling Glycosidase and Glycosyltransferase Activities 100
6.5.3 Inhibitor-Based Probes for Modulating Carbohydrate Metabolism 101
6.5.4 Probes for Imaging Carbohydrate Metabolism in Vivo 101
6.6 Conclusion 102
Questions 103
References 103
7 Metals and Metalloprotein 104
7.1 Introduction to Metal Ions and Their Biological Importance 105
7.2 Essential Elements and Trace Metals 106
7.2.1 Essential Elements 106
7.2.2 Trace Metals 107
7.3 Functional Role of Metals in Biology 108
7.3.1 Role of Metals in Hydrolytic Reactions 108
7.3.2 Metals in Electron Transfer 109
7.4 Metal Catalyzed Oxygen Activation 109
7.4.1 Oxygen Activation by Transition Metals 111
7.4.2 Biological Implications of Metal-Mediated Oxygen Activation 112
7.5 Iron and Heme Proteins 112
7.5.1 Structure and Function of Heme 113
7.5.2 Oxygen Transport：Hemoglobin and Myoglobin 113
7.5.3 Electron Transfer：Cytochromes 114
7.5.4 Catalysis：P450 Monooxygenases 114
7.6 Conclusion 115
Questions 117
References 117
8 Bio-orthogonal Reaction 119
8.1 Definition and Principles 121
8.2 Bio-orthogonal Reactions 123
8.2.1 The Staudinger Ligation 123
8.2.2 Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) 125
8.2.3 Strain-Promoted Azide-Alkyne Cycloaddition 125
8.2.4 Tetrazine Ligation 126
8.2.5 Oxime and Hydrazone Formation 127
8.2.6 Photoinduced Bio-orthogonal Reactions 128
8.2.7 Metal-Mediated Bio-orthogonal Reactions 130
8.3 Applications of Bio-orthogonal Chemistry 131
8.3.1 Molecular Imaging and Labeling 131
8.3.2 Drug Delivery and Therapeutics 131
8.3.3 In Vivo Chemical Biology 132
8.4 Conclusion 133
Questions 134
References 134
9 Orthogonality in Biological Systems 135
9.1 Semantic and Alphabetic Orthogonality 137
9.2 Orthogonality in Translation Systems 138
9.2.1 Orthogonal tRNA and Aminoacyl-tRNA Synthetase Pairs 139
9.2.2 Orthogonal Ribosomes 140
9.3 Orthogonal Replication and Transcription System 140
9.3.1 Orthogonal DNA Replication Systems 141
9.3.2 Design and Implementation of Orthogonal Transcription Systems 141
9.4 Genetic Code Expansion 143
9.4.1 Reassigning Stop Codons 143
9.4.2 Quadruplet Codon Systems 147
9.4.3 Genome Redesign 147
9.4.4 Applications of Unnatural Amino Acids 148
9.5 Mirror-Image System 150
9.6 Expansion of the Genetic Alphabet 152
9.7 Conclusion 153
Questions 154
References 155
10 Sequencing and Biological Databases 156
10.1 Nucleic Acid Sequencing and the Omics 158
10.1.1 Sanger Sequencing：The Foundation of Genomics 158
10.1.2 The Human Genome Project：A Milestone in Genomic Research 159
10.1.3 Next-Generation Sequencing：High-Throughput Genomics 160
10.1.4 The Third-Generation Sequencing：Long Reads for Genomics Study 160
10.1.5 Metagenomics：Exploring the Microbial World 161
10.2 Protein Sequencing 162
10.2.1 Historical Context and Edman Degradation 162
10.2.2 Mass Spectrometry-Based Protein Sequencing 163
10.2.3 Nanopore Sequencing of Proteins 164
10.3 Biological Databases 165
10.3.1 GenBank：A Comprehensive Nucleotide Sequence Database 169
10.3.2 UniProt：The Universal Protein Resource 169
10.3.3 PDB：The Protein Data Bank 170
10.3.4 KEGG：Kyoto Encyclopedia of Genes and Genomes 171
10.3.5 BRENDA：The Comprehensive Enzyme Information System 171
10.3.6 Databases in the AI era 172
Questions 172
References 173
11 Protein Structure Prediction 174
11.1 Protein Folding 176
11.2 Computational Methods for Protein Structure Prediction 179
11.2.1 Molecular Dynamics Simulations 180
11.2.2 Homology Modeling and Threading 181
11.2.3 Rosetta 182
11.2.4 Critical Assessment of Structure Prediction (CASP) 184
11.3 AI Methods in Protein Structure Prediction 185
11.3.1 AlphaFold2：A Landmark Achievement 186
11.3.2 Protein Language Models and Structure Prediction 187
11.3.3 Other Structure Prediction Methods and Recent Advances 189
11.4 Impact of AI-Based Protein Structure Prediction 190
11.4.1 Establishment of Structural Databases 190
11.4.2 Transformation from Sequence-Based to Structure-Based Methods 191
11.5 Conclusion 191
Questions 192
References 193
12 Molecular Evolution and Directed Evolution 194
12.1 Natural Evolution 195
12.1.1 The Principles of Natural Evolution 195
12.1.2 From Natural to Directed Evolution 196
12.2 Evolution of Biomacromolecules 197
12.2.1 Phylogenetic Tree：Tracing Evolutionary Relationships 197
12.2.2 Information from Molecular Evolution and Rich Sequence Data 197
12.2.3 Ancestral Sequence Reconstruction 198
12.2.4 Amino Acid Coevolution 198
12.2.5 Evolution as a Searching Algorithm 199
12.3 Directed Evolution：Accelerating Natural Processes 200
12.3.1 Methods for Introducing Variation 201
12.3.2 Amplification and Linking of Gene Libraries 202
12.3.3 Screening and Selection 205
12.4 AI-Assisted Directed Evolution 207
12.4.1 Machine Learning in Directed Evolution 208
12.4.2 Protein Language Models 208
12.5 In Vivo Directed Evolution 209
12.5.1 Principles of In Vivo Directed Evolution 210
12.5.2 Examples of In Vivo Directed Evolution Systems 210
12.6 Conclusion 211
Questions 212
References 212
13 Protein Computational Design 214
13.1 Protein Sequence Space and Fitness Landscape 215
13.1.1 Exploring the Fitness Landscape 215
13.1.2 Schemes of Computational Design 217
13.2 Design Strategies：De Novo vs. Redesign 220
13.2.1 De Novo Protein Design 220
13.2.2 Protein Redesign and Mutation 220
13.2.3 Biochemical and Structural Biology Knowledge in Protein Design 223
13.3 Protein Design：An Overview 223
13.3.1 Historical Context 223
13.3.2 Peptide Design 224
13.3.3 Rosetta in Protein Design 226
13.4 Deep Learning-Based Methods in Computational Protein Design 227
13.4.1 The Inverse Folding Problem and Sequence Design 227
13.4.2 Backbone Design 229
13.4.3 Sequence-Structure Co-Design 231
13.4.4 Strategies toward Designing Function 232
13.5 Conclusion 237
13.5.1 Interplay of Experiment and Computation 238
13.5.2 Database for Training 238
13.5.3 Integration with Directed Evolution 239
13.5.4 Multimodal Design 239
Questions 240
References 241
14 Chemical Genetics 243
14.1 Classical Genetics 244
14.1.1 Forward Genetics 245
14.1.2 Reverse Genetics 245
14.2 Protein-Small Molecule Interactions 246
14.3 Principles of Chemical Genetics 248
14.3.1 Forward Chemical Genetics 248
14.3.2 Reverse Chemical Genetics 250
14.3.3 Methodologies in Chemical Genetics 251
14.4 Chemical Genetics in Drug Discovery 254
Questions 256
References 256
15 Biocatalysis 258
15.1 Chemo-enzymatic Catalysis 260
15.2 Artificial Enzymes 263
15.3 Photocatalysis 266
15.3.1 Strategies for Combining Biocatalysis and Photocatalysis 266
15.3.2 Repurposing Natural Photoenzymes 268
15.3.3 Elucidating New Photoreactivity Within Cofactor-Dependent Enzymes 268
15.3.4 Synergistic Combination of External Photocatalysis and Enzymes 269
15.3.5 Construction of Artificial Photoenzymes 269
15.4 Biocatalysis with Functional Materials 270
15.5 Conclusion 271
Questions 272
References 273
16 Biopharmaceuticals 275
16.1 Introduction to Biopharmaceuticals 276
16.2 Categories of Biopharmaceuticals 277
16.2.1 Biocatalysis and Biotransformation Products 277
16.2.2 Biomacromolecules 278
16.2.3 Cells and Cell Components 278
16.3 Case Studies in Biopharmaceuticals 279
16.3.1 Insulin as a Pioneering Biopharmaceutical 279
16.3.2 Biocatalysis in the Synthesis of Sitagliptin 282
16.3.3 Monoclonal Antibodies Engineering 283
16.3.4 CAR-T Therapy：A New Frontier in Cancer Treatment 285
16.4 Conclusion 287
Questions 288
References 288
新书资讯
