Exploration of conformational transition in the aryl-binding site of human FXa using molecular dynamics simulations.

Human coagulation Factor X (FX), a member of the vitamin K-dependent serine protease family, is a crucial component of the human coagulation cascade. Activated FX (FXa) participates in forming the prothrombinase complex on activated platelets to convert prothrombin to thrombin in coagulation reactions. In the current study, 30-ns MD simulations were performed on both the open and closed states of human FXa. Root mean squares (RMS) fluctuations showed that structural fluctuations concentrated on the loop regions of FXa, and the presence of a ligand in the closed system resulted in larger fluctuations of the gating residues. The open system had a gating distance from 9.23 to 11.33 Å, i.e., significantly larger than that of the closed system (4.69-6.35 Å), which allows diversified substrates of variable size to enter. Although the solvent accessible surface areas (SASA) of FXa remained the same in both systems, the open system generally had a larger total SASA or hydrophobic SASA (or both) for residues surrounding the S4 pocket. Additionally, more hydrogen bonds were formed in the closed state than in the open state of FXa, which is believed to play a significant role in maintaining the closed confirmation of the aryl-binding site. Based on the results of MD simulations, we propose that an induced-fit mechanism governs the functioning of human coagulation FX, which helps provide a better understanding of the interactions between FXa and its substrate, and the mechanism of the conformational changes involved in human coagulation.