Jiajie Xiao, PhD Candidate
Public Presentation in Olin Physics Building, Room 101
Friday, June 15, 2018, at 1:oo PM
Fred Salsbury, PhD, Advisor
The defense will follow.
Thrombin is an attractive drug target for antithrombotic therapy and chemotherapeutic development due to its critical role in blood coagulation, as well as in cancer cell growth and metastasis. Many experiments have demonstrated that thrombin is a multifunctional allosteric enzyme, whose functions are regulated by the binding of effector molecule at a site other than the active site of the enzyme. However, the exact mechanism of thrombin’s allostery remains unclear and widely debated.
This work describes my application of molecular dynamics simulations and various quantitative methods to uncover thrombin’s allostery. It discusses thrombin’s allosteric responses to different factors including ion conditions, disease-associated mutations, and ligation statuses. My in-depth atomic-level investigation presents experimentally consistent results and provides mechanistic insights into thrombin’s functional switch. The generalized allostery should be the main mechanism of thrombin’s functional regulations. Several novel testable predictions further the understanding of thrombin’s substrate recognition process and allosteric pathways. The allosteric responses revealed in this work may be exploited in further drug discovery and development.