Factor V (FV) is a key regulatory protein in the coagulation cascade, maintaining the balance between normal hemostasis and excessive clot formation. FV remains inactive in circulation until thrombin converts it into active factor Va (FVa), which is required for clotting. Under normal conditions, clotting is regulated by the activated protein C and protein S complex (APC: PS), which inactivates FVa through cleavage at residues Arg306, Arg506, and Arg679. In the case of factor V Leiden (FVL), a single-point mutation replaces arginine with glutamine at residue 506 (R506Q), disrupting the regulation and increasing the risk of abnormal clotting. Currently, no specific cure exists for FVL, and current treatment relies on non-specific anticoagulants. Molecular modeling was performed to characterize the stability of APC and PS and the specific binding interactions of the APC: PS complex. Missing regions in the PS crystal structure (PDB 1Z6C) were modeled with SWISS-MODEL, and ten γ-carboxyglutamic acid (GLA) residues were incorporated to reflect in vivo posttranslational modifications. Molecular dynamics simulations (1000 ns, triplicate) were performed to assess the stability and conformational dynamics of each protein individually and of the docked protein-protein APC: PS complex. Assessments for structural stability, surface accessibility, and binding free energies were conducted on APC and PS separately, as well as the bound APC: PS complex. Preliminary results indicate favorable and stable binding between APC and PS, supporting their integral role in FVa regulation. Ongoing simulations aim to characterize the interactions between FVa and APC: PS. These results provide insight into how the APC: PS complex deactivates blood clotting and may inform the design of future targeted therapies for the FVL mutation.
Brown et al. (Sun,) studied this question.