DNA Topology and Mechanics

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The overall goal of my thesis is to enhance our quantitative understanding of the biophysical properties of DNA a long polynucleotide chain, present in every living cell, that embodies the genetic information. The existence of DNA has been known to us for over a century, however, our understanding of its physiochemical nature and spatial organization inside our cells is ever evolving. Since the momentous discovery of the double-helical structure of DNA, the emergent view of DNA as a long biopolymer that proteins manipulate via physical interactions has been very successful in explaining experimental observations and proposing biological mechanisms. Since DNA resides in an environment where thermal fluctuations are omnipresent, statistical-mechanical properties of DNA play an indispensable role in protein-DNA interactions. Topological constraints are an essential feature of cellular DNA. Active control of both the intra-DNA topology, arising from the double-helix structure, and the inter-DNA topology due to its long length and self-avoidance, is an important characteristic of various biological functions. This dissertation contains theoretical models of double-helix DNA and other biologically-relevant DNA structures, such as two intertwined DNAs, where we view the double helix as a semiflexible elastic rod or a worm-like chain with an inherent twist stiffness. Our results explain torsion-induced buckling in stretched double-helix DNAs and intertwined DNAs that are in good quantitative agreement with existing experiments. New experimental data, resulting from collaborations, that successfully verified theoretical predictions are also reported. Some of our novel findings shed light on the role of certain structural defects in modulating DNA-buckling behavior, and the influence structural bulkiness may have on the stability of buckled DNAs. We also address a long-standing question of topological simplification of cellular chromosomes via modeling chromosome as a polymer bottle-brush or a cylindrical array of DNA loops. Our finding, inter-chromosome entanglements can be minimized by an optimal-loop length, may suggest that chromosome domains in interphase nuclei or Topologically Associating Domains (TADs) play a role in entanglement minimization. Loop extrusion, that has been recently proposed as a mechanism to compact chromosomes during the cell cycle, provides an active process to control the compaction state of chromosomes within our model. Our model of loop-extruded chromosome is quantitatively consistent with experiments reporting the rigidity modulus in chromosomes, which in our case, derives from a cylindrical core of densely packed DNA. The theoretical models described here make testable predictions, that we hope, will help design future experiments and uncover new phenomena, creating a need for novel theoretical techniques.

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  • 11/20/2019
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