Structural insights into the activation of blood coagulation factor XI zymogen by thrombin: A computational molecular dynamics study.

Activation of human blood coagulation factor XI zymogen to factor XIa plays a significant role in the upstream coagulation pathway, in which factor XIa activates factor IX zymogen. The mechanistic details of the proteolytic activation of factor XI by the activating enzyme thrombin are not well-understood at atomic level. In this study, we employed a combination of molecular docking and microsecond time-scale molecular dynamics simulations to identify the key regions of interaction between fXI and thrombin. The activating complex between the substrate and enzyme was modeled to represent the initial acylation step of the serine-protease hydrolysis mechanism. The proposed solution structural complex, fIX:fIIa, obtained from 3 microseconds of MD refinement, suggests that the activation of factor XI is mediated by thrombin's anion binding exosite-II interactions with A3 and A4 domains. We predict that the two positively charged arginine residues (Arg409 and Arg413) in the exosite-2 region, the β- and γ-insertion loops of thrombin play an important structural role in the initial activating complex between fXI and thrombin.