Re-Inventing Template-Directed Replication in Dynamic Chemical Networks Open Access

Zhang, Li (2016)

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Biological replication, either sequence replication defined by the Central Dogma, or prion conformational replication, is driven by a template-directed mechanism. Previous efforts to re-invent templated replication in non-enzymatic systems were unsuccessful partly due to the lack of reversibility. Dynamic chemical networks (DCNs) provide a remarkable platform for selection of replicating species in a dynamic manner, and with adaptive and evolvable potential towards changing environments. Dynamic chemical networks were constructed using reversible N,O-acetal condensation. Model study establishes dynamic properties, environment impacts and stereochemistry of N,O-acetal condensation reaction, providing insight for our design of networks. DNA templated sequence information transfer in ribose-amine nucleoside polymer (rANP) networks was accomplished, with B-form duplex formed between template and rANP oligomers. Peptide networks based on TTF-CHO building block were generated, with cyclic dimer being selected as major species, and under certain condition self-assembled into novel structures. Prion-like templated conformational replication behavior was achieved in a TTF-CHO + (TTF)2 network, in which both self-templated and external-templated conformation replication were selected and propagated into different assembly structures. These discoveries achieved selection for replication behavior in dynamic chemical networks by generating diversity on both chemical and physical levels. More importantly, the common reversible linkage that connects both informational biopolymers of biology provides a unique form of nucleic acid/amino acid symbiosis for the emergence of chemical evolution.

Table of Contents

Chapter One

Templated Information Replication in Dynamic Chemical Networks 1

1.1 Template-Directed Replication in Biological Selection and Evolution 1

1.2 Re-Inventing Template-Directed Replication 4

1.3 Dynamic Chemical Networks (DCNs) and Template Effect 8

1.4 Re-Invent Template-Directed Replication in DCNs 12

Chapter Two

Investigating Dynamic N,O-acetal Condensation on Nucleic Acid and Peptide Backbones 27

2.1 Introduction 27

2.1.1 From dANP to rANP: Use of N,O-acetal Linkage 27

2.1.2 Extending N,O-acetal Linkages on Peptide Backbones 29

2.1.3 Stereo-Selectivity in N,O-acetal Condensation 30

2.2 Results and Discussion 31

2.2.1 N,O-acetal on rANP Backbone 31

2.2.2 Kinetics of N.O-acetal Condensation on rANP Dimer 33

2.2.3 Kinetics of N, O-acetal Hydrolysis on rANP Dimer 36

2.2.4 Stereochemistry Assignment of Diastereomers 38

2.2.5 N,O-acetal Condensation and Kinetics on Peptide Backbones 40

2.2.6 Diastereoselectivity of N,O-acetal Condensation on Peptide Backbone 43

2.3 Conclusion 44

2.4 Experimental 46

2.4.1 General Methods 46

2.4.2 Synthesis of 3'-CHO-5'-Tr-Uridine (7u) 46

2.4.3 Synthesis of 2'-, 3'- di-TBS - 5'-Amino Uridine (11u) 52

2.4.4 Mixing of 7u with 11u for N, O-acetal Condensation 56

2.4.5 Preparation of Free Amine Substrates by Neutralizing Thr Ester HCl Salts 56

2.4.6 Mixing of Thr Ester with Phe Aldehyde for N, O -acetal Product 57

Chapter Three

DNA Templated rANP Networks: Formation of DNA/rANP Duplexes 61

3.1 Introduction 61

3.2 Results and Discussion 64

3.2.1 Synthesis of rANP Monomer Building Blocks 64

3.2.2 (dA)16 Template in rANP Networks Induces DNA/rANP Hybrid Duplexes 67

3.2.3 Kinetics of Duplex Formation in Templated rANP Networks 72

3.2.4 Thermal Melting Experiments Suggest High Duplex Binding Affinity 74

3.2.5 Impact of Template Length on Duplex Formation 76

3.2.6 Impact of pH on DNA Templated ANP Oligomerization 76

3.2.7 Impact of Ionic Strength on DNA Templated ANP Oligomerization 78

3.3 Conclusion 80

3.4 Experimental 82

3.4.1 Synthesis of rANP Monomer rU1 82

3.4.2 Synthesis of rANP Monomer rU2 87

3.4.3 DNA Templated ANP Networks 95

Chapter Four

TTF-CHO Networks: Environmental Impacts and Self-Assembly 102

4.1 Introduction 102

4.2 Results and Discussions 104

4.2.1 Construction of Dynamic Chemical Networks from TTF-CHO 104

4.2.2 Environmental Conditions Control Behavior of TTF-CHO DCNs 109

4.2.3 Characterization of Cyclic Dimer Structure 115

4.2.4 Cyclic Dimer Fibers Emerge in TTF-CHO DCN 118

4.3 Conclusion 123

4.4 Experimental 125

4.4.1 General Methods 125

4.4.2 Synthesis of TTF-CHO 127

4.4.3 Dynamic Chemical Networks 133

Chapter Five

TTF-CHO + (TTF)2 Network: Self-templated and External Templated Replication 138

5.1 Introduction 138

5.2 Results and Discussion 140

5.2.1 Understanding (TTF)n Peptide Self-Assembly 140

5.2.2 Structural Characterization of (TTF)3 nanotubes 142

5.2.2 Selecting Linear Trimer TTFoxTTFTTF from TTF-CHO + (TTF)2 Network 146

5.2.3 Self-Templated Propagation in TTF-CHO + (TTF)2 Network 149

5.2.4 Kinetics of TTF-CHO + (TTF)2 DCN 155

5.2.5 External Template Guides DCN to New Self-Assembly Structure 159

5.2.6 Structural Characterization of Nanotubes in External Templated DCN. 164

5.3 Conclusion 167

5.4 Experimental 168

5.4.1 General Methods 168

5.4.2 Dynamic Chemical Networks 172

Chapter Six

Summary and Outlook 176

6.1 Summary 176

6.2 Outlook 178

6.2.1 One Common Linkage for Two Biopolymers 178

6.2.2 Enriching Inventory Complexity of DCN Building Blocks 179

6.2.3 Selection of Functions in Dynamic Chemical Networks 180

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