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UNDERSTANDING GENERALIZED ALLOSTERY IN THROMBIN

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abstract
Thrombin is a critical drug target for chemotherapeutic and antithrombotic therapy development. Although many experiments have demonstrated that thrombin is a multifunctional allosteric enzyme, the exact mechanism of thrombin's allostery is still unclear and widely debated. This dissertation describes my application of molecular dynamics simulations and various quantitative methods to uncover thrombin's allostery. It discusses thrombin's allosteric responses upon different factors including ion conditions, mutations, and ligation statuses. My in-depth atomic-level investigation presents experimentally consistent results and also provides mechanistic insights into thrombin's functional switch. Several novel testable predictions further the understanding of thrombin's substrate recognition process and allosteric pathways. Finally, the work concludes with future directions of investigating the allosteric network of thrombin.
subject
Allostery
Biophysics
Machine learning
Molecular dynamics simulations
Thrombin
contributor
Xiao, Jiajie (author)
Salsbury, Freddie R (committee chair)
Turkett, William H (committee member)
Bonin, Keith D (committee member)
Guthold, Martin (committee member)
Kim-Shapiro, Daniel B (committee member)
date
2018-08-23T08:35:30Z (accessioned)
2019-08-22T08:30:15Z (available)
2018 (issued)
degree
Physics (discipline)
embargo
2019-08-22 (terms)
identifier
http://hdl.handle.net/10339/92371 (uri)
language
en (iso)
publisher
Wake Forest University
title
UNDERSTANDING GENERALIZED ALLOSTERY IN THROMBIN
type
Dissertation

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