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.

Structural insights into the interaction of blood coagulation co-factor VIIIa with factor IXa: a computational protein-protein docking and molecular dynamics refinement study.

Coagulation factor X (FX) zymogen activation by factor IXa (FIXa) enzyme plays a critical role in the middle-phase of coagulation cascade. The activation process is catalytically inert and requires FIXa binding and complex formation with co-factor VIIIa (FVIIIa). In order to understand the structural details of the FVIIIa:FIXa complex, we employed knowledge-driven protein-protein docking and aqueous-phase MD refinement methods to develop a stable structural complex between FVIIIa and FIXa.

Role of hydrophobic mutations on the binding affinity and stability of blood coagulation factor VIIIa: a computational molecular dynamics and free-energy analysis.

Factor VIIIa is a non-covalently bound hetero-trimer among A1, A2 and A3-C1-C2 domains and an essential co-factor for factor IXa enzyme during proteolytic activation of factor X zymogen. The relatively weak interactions between A2 and the interface A1/A3 domains dampen the functional stability of FVIIIa in plasma and results in rapid degradation. We studied the mutational effect of three charged residues (Asp519, Glu665 and Asp666) to several hydrophobic residues by molecular dynamics simulations.

Structural investigation of zymogenic and activated forms of human blood coagulation factor VIII: a computational molecular dynamics study.

Background: Human blood coagulation factor VIII (fVIII) is a large plasma glycoprotein with sequential domain arrangement in the order A1-a1-A2-a2-B-a3-A3-C1-C2. The A1, A2 and A3 domains are interconnected by long linker peptides (a1, a2 and a3) that possess the activation sites. Proteolysis of fVIII zymogen by thrombin or factor Xa results in the generation of the activated form (fVIIIa) which serves as a critical co-factor for factor IXa (fIXa) enzyme in the intrinsic coagulation pathway.

Three-dimensional solution structure of Tropidechis carinatus venom extract trocarin: a structural homologue of Xa and prothrombin activator.

Trocarin belongs to group D of prothrombin activators derived from snake venom of Tropidechis carinatus and is a rich non-hepatic source of Xa, the only known hepatic prothrombin activator. The structural and functional similarity with Xa makes trocarin an interesting target for exploring the structure-functional relationship with Xa. Herein we report a predicted complete three-dimensional all-atom structural model of trocarin equilibrated in explicit water using 4 ns of molecular dynamics simulation.

Structure and dynamics of zymogen human blood coagulation factor X.

The solution structure and dynamics of the human coagulation factor X (FX) have been investigated to understand the key structural elements in the zymogenic form that participates in the activation process. The model was constructed based on the 2.3-A-resolution x-ray crystallographic structure of active-site inhibited human FXa (PDB:1XKA).