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.

Computational analysis of Asp519 and Glu665 mutations of coagulation factor FVIIIa: Implications for enhanced binding affinity of A2-domain.

The A2-domain of blood coagulation factor VIIIa is non-covalently bound to the A1 and A3 domains via weak intermolecular interactions. Functional instability due to rapid dissociation of A2-domain from the active FVIII in blood presents a major hurdle for the therapeutic applications of FVIIIa to treat Hemophilia-A. To identify the ideal hot-spot residues at the interface of A2 and A1/A3 domains that could enhance the structural stability of FVIIIa, we performed a comprehensive computational mutagenesis study of two A2-domain residues, Asp519 and Glu665, that interface the A1 and A3-domains.