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 present the solution structure obtained by 1.5 microseconds of molecular dynamics refinement of the homodimer of fXI:fXI structure. Based on the protein-protein docking approach, we propose the structural model for the interactions of thrombin enzyme with fXI zymogen that represents the Michalis complex of the initial acylation step of the serine-protease hydrolysis. The proposed complex model between the thrombin enzyme and fXI substrate reveals that the activation of fXI by thrombin is mediated by anion binding exosite-2 (ABE2) interactions with A3 and A4 domains. We predict that Arg409 and Arg413 of ABE-2 play critical role in mediating the interaction of thrombin with fXI. The insertion loop 60 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 ABE-2 of thrombin.<br/>

Solution structure of FXI:FXI dimer and activation mechanism by thrombin: A molecular docking and MD refinement study

255th National Meeting (2018)

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