Structural Insights into the Activation of Blood Coagulation Factor XI Zymogen by Thrombin: A Computational Molecular Dynamics Study

Abstract

Activation of human blood coagulation factor XI zymogen into fXIa plays a significant role in the upstream coagulation pathway in which fXIa activates fIX zymogen into active fIX. The mechanistic details of how fXI gets activated by the key activating enzyme thrombin are not well-understood at atomic level, despite a wealth of reported experimental biochemical data. In this study, we provide a structural model for the interactions of thrombin enzyme with FXI zymogen that represent the initial acylation step of the serine-protease hydrolysis by employing protein-protein docking and explicit-solvent MD simulations for 2 microseconds. The proposed complex model between the thrombin enzyme and FXI substrate reveals that the activation of FXI is mediated by thrombin's anion binding exosite-2 (ABE2) interactions with A3 and A4 domains. We predict that Arg409 and Arg413 of ABE2 play critical role in mediating the interaction of thrombin with FXI. The insertion loop 60 of thrombin is also seen to interact with both apple and SP domains of FXI. The binding free-energy of interaction of the wild-type and four mutants of FXI with thrombin are also estimated to ascertain the relative importance of ABE2 of thrombin.