Date of Award

Winter 3-2-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Physics

First Advisor

Thomas Bishop

Abstract

Nucleosomes are the building blocks of eukaryotic genomes and thus fundamental to to all genetic processes. Any protein or drug that binds DNA must either cooperate or compete with nucleosomes. Given that a nucleosome contains 147 base pairs of DNA, there are approximately 4^147 or 10^88 possible sequences for a single nucleosome. Exhaustive studies are not possible. However, genome wide association studies can identify individual nucleosomes of interest to a specific mechanism, and today's supercomputers enable comparative simulation studies of 10s to 100s of nucleosomes. The goal of this thesis is to develop and present and end-to-end workflow that serves as a solution for comparative, on-demand simulation studies of nucleosomes. This project provides integrated data managing, a sharing solution, new analysis metrics to investigate DNA kinking, the analysis of nucleosome geometry, and clearly demonstrates the effects of DNA sequence on the gross structure and dynamics of nucleosomes. To achieve this goal, we must develop 1) an integrated data managing and sharing solution; 2) a metric for nucleosomal analysis; and 3) a standard reference for nucleosome geometry. This allows us to determine the effect of DNA sequence on the structure of nucleosomes and the nucleosome positioning. The workflow supports the selection of DNA sequences based on informatics, on-demand overnight simulation of nucleosomes, comparative studies of trajectory analyses, data management and sharing, and analyses of the structure. There are five chapters in this thesis. Chapter 1: Introduction, necessary background and preliminary work by Ran Sun during his Master's research; Chapter 2: TMB Library as a solution to data management and sharing; Chapter 3: New analysis metrics of nucleosomal DNA that reveals the sequence effect on positioning and mispositioning of nucleosomes; Chapter 4: The structural analysis of the nucleosome geometry which defines a standard reference for nucleosome modeling; Chapter 5: The end-to-end workflow, NuModeller, integrates all tools and components from above into a Python based package as a sustainable package for the lab.

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