EXTENDING THE CENTRAL DOGMA: DEVELOPING NOVEL INFORMATIONAL BIOPOLYMERS Open Access

Abstract

In biology, the highly accurate replication of sequence information encoded on informational biopolymers is accomplished by template-directed polymerization with sophisticated polymerases. Decades of efforts have been put into creating simple chemical systems to mimic such processes. By replacing phosphodiester with reversible imines, we created a dynamic nucleoside chemical network (DCN) as a very simple model that were managed by sophisticated biological catalyst. We have successfully achieved template-directed polymerization to synthesize amine nucleoside polymers (ANPs) with high fidelity. The diversity of ANP-based DCNs provides for potential emergent functions. Leveraging the catalytic activity of the amine backbone, we developed dANP-based ANPzymes as novel gene regulation platforms. We further constructed DCNs with full potential to respond to different environmental inputs and templates. Finally, taking advantage of dynamic chemical networks and templating effects, we set the stage for re-directing information transfer behavior in chemical systems through computational modeling of those processes.

Table of Contents

Table of Contents

Chapter 1: Amine Nucleoside Polymer Enzyme (ANPzyme) as a Novel Gene Therapy Platform..1

1.1 Introduction. 1

1.1.1 Gene Therapy for Neuro-degenerative Diseases. 1

1.1.2 Challenges for Current Gene Therapeutics. 2

1.1.3 Development of Amine Nucleoside Polymers(ANPs). 3

1.1.4 Utilizing the ANPs as Novel Genetic Regulations. 4

1.1.5 ANP ligation enzyme. 5

1.2 Results & Discussion. 7

1.2.1 Obtain ANP Oligomers and Characterize Their Biological Properties. 7

1.2.2 Prove Cellular Uptake in Jurkat Cells. 14

1.2.3 Develop an ANPzyme Able to Cleave mRNA.. 17

1.3 Conclusion & Future Directions 30

Chapter 2: Understanding Conformational Evolution of Dynamic Chemical Library by Computational Simulation..31

2.1 Introduction. 31

2.1.1 Nucleic Acid Dynamic Chemical Networks with reversible imine linkage. 31

2.1.2 Extending Reversible Acetal linkages to Peptide Dynamic Chemical Networks. 34

2.1.3 Understanding Stereochemistry in Acetal Chiral Centers. 35

2.1.4 Study Structural Information by Molecular Dynamics. 37

2.2 Results and Discussion. 39

2.2.1 Understanding Conformational Evolution of Dynamic Chemical Network by Molecular (MD) Simulations 39

2.2.2 Analyze DCN Composition by Machine Learning Algorithms. 43

2.2.3 Characterize the Supramolecular Assemblies. 44

2.3 Conclusion & Future Directions 51

2.4 Methods 52

2.4.1 Materials. 52

2.4.2 Synthesis of NF-CHO.. 52

2.4.3 Synthesis of NFF-CHO.. 57

2.4.4 NMR Analysis. 61

2.4.5 Dynamic Peptide Network Preparation. 61

2.4.6 HPLC and LC-MS Analyses. 62

2.4.7 Transmission Electron Microscopy and Electron Diffraction. 62

2.4.8 Microwave Assisted Solid-Phase Peptide Synthesis. 63

References.. 65

About this Master's Thesis

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School	Laney Graduate School
Department	Chemistry
Degree	MS
Submission	Master's Thesis
Language	English
Research Field	Chemistry, Molecular Computer Science Chemistry, General
Keyword	amine nucleoside polymer molecular dynamics dynamic chemical network biololymers gene therapy computational chemistry machine learning
Committee Chair / Thesis Advisor	Lynn, David, Emory University
Committee Members	Weinert, Emily E, Emory University McDonald, Frank, Emory University

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