BPS2026 – Computationally modeling structural changes in the factor V Leiden mutation to prevent blood clot disorders

Factor V (FV) is a critical blood-clotting protein of the coagulation system. This inactive form circulates the blood stream until needed, then is activated to factor Va (FVa) by thrombin, exposing binding sites of the protein. FVa can be deactivated by a complex of activated protein C and protein S (APC:PS) cleaving FVa at residues R306, R506, and R679, inhibiting the coagulation cascade. A single amino acid mutation from an arginine to a glutamine at residue 506 causes factor V Leiden (FVL), which impairs the binding of APC:PS to FVa, therefore increasing the likelihood of abnormal blood clots. There is currently no cure for this mutation—only anticoagulant drugs are prescribed. We analyzed the binding site of FVa and APC:PS to further study this mutation and potentially develop a specific treatment for FVL. Using computational methods such as molecular docking with HADDOCK and molecular dynamics with Amber, we observe the binding interactions between the different protein-protein systems. Preliminary results suggest the wild type and representative mutant structure are distinct, with a root mean square deviation value of 7.57 Å. Additionally, the Leiden mutant forms a less stable complex with APC, with the FVa:APC average binding energy at −77.2 kcal/mol, and the average binding energy of the FVL:APC at −60.5 kcal/mol, both simulated for 1000 ns. Furthermore, we have simulated and analyzed FVa:APC:PS and FVL:APC:PS, and determined the important amino acid binding sites to characterize, compare, and contrast the interactions between the wild type and mutant complexes. Future work involves evaluating structural changes in FVa by ligands in the potential development of a specific treatment for the Factor V Leiden mutation.