Simulating the Mechanics of Protein-Induced DNA Looping and Protein-Constrained DNA Buckling.
dc.contributor.author | Hirsh, Andrew D. | en_US |
dc.date.accessioned | 2013-09-24T16:01:49Z | |
dc.date.available | NO_RESTRICTION | en_US |
dc.date.available | 2013-09-24T16:01:49Z | |
dc.date.issued | 2013 | en_US |
dc.date.submitted | 2013 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/99845 | |
dc.description.abstract | The bending and twisting mechanics of DNA are known to play a crucial role in many biological processes, yet fundamental details, even in relatively simple systems, remain unclear. The overall objective of this dissertation is to advance this knowledge in the context of two important systems including 1) the role of protein flexibility in an elementary gene regulatory protein that loops DNA, and 2) the structure and biological function(s) of DNA buckling during packaging and ejection in bacterial viruses. To address this objective, we contribute new modeling techniques by extending an elastic rod model for DNA. For protein-induced DNA looping, we use the model to reinterpret two seminal studies on Lac repressor looped DNA including the stability and topology of loops. For viral packaging, we contribute a model for mechanical contact between DNA and a cavity of arbitrary geometry, and also the first multi-scale model for DNA under extreme compression, to examine a buckled DNA toroid recently discovered in a protein cavity below the bacteriophage phi29 viral capsid. This example further motivates an extensive study of the mechanics of constrained DNA buckles inside the portal cavities of a family of viruses. The theoretical results for looped DNA successfully predict experimental observations and reveal that an extended protein conformation was active, yet overlooked, in classic experiments by the Muller-Hill laboratory. A detailed analysis of phi29 reveals that a DNA toroid can form under biologically-relevant force levels supplied by a packing motor. Computed DNA density maps compare favorably with the experimental data. Upon simulating the dynamic ejection of the toroid from the cavity, we reveal that large reaction forces/torques develop at the portal that could be used to signal genome release. Using Greenhill's equation, we show that DNA buckling is also feasible in a number of other bacteriophages including T7 and P22 that contain large portal cavities. Simulating DNA buckles in these cavities shows that large reaction forces develop on the portal walls that could signal a motor to terminate packing. Despite differences in size and shape, the cavities possess the same energy density. | en_US |
dc.language.iso | en_US | en_US |
dc.subject | DNA Mechanics | en_US |
dc.subject | DNA Looping | en_US |
dc.subject | DNA Buckling | en_US |
dc.subject | Viral DNA Packaging | en_US |
dc.title | Simulating the Mechanics of Protein-Induced DNA Looping and Protein-Constrained DNA Buckling. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Mechanical Engineering | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Perkins, Noel C. | en_US |
dc.contributor.committeemember | Meyhofer, Edgar | en_US |
dc.contributor.committeemember | Brooks Iii, Charles L. | en_US |
dc.contributor.committeemember | Epureanu, Bogdan | en_US |
dc.contributor.committeemember | Andricioaei, Ioan | en_US |
dc.subject.hlbsecondlevel | Mechanical Engineering | en_US |
dc.subject.hlbtoplevel | Engineering | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/99845/1/adhirsh_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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