UNDERSTANDING GENERALIZED ALLOSTERY IN THROMBIN

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.