Atomistic Mechanism of Lipid Membrane Binding for Blood Coagulation Factor VIII with Molecular Dynamics Simulations on a Microsecond Time Scale.

During the blood coagulation cascade, coagulation factor VIII (FVIII) is activated by thrombin to form activated factor VIII (FVIIIa). FVIIIa associates with platelet surfaces at the site of vascular damage to form an intrinsic tenase complex with activated factor IX. A working model for FVIII membrane binding involves the association of positively charged FVIII residues with negatively charged lipid headgroups and the burial of hydrophobic residues into the membrane interior. Currently, the atomic details of the FVIII lipid binding interactions and membrane orientation are lacking. This study reports residue-specific FVIII C domain interactions with 1,2-dioleoyl--glycero-3-phosphocholine (DOPC) and 1,2-dioleoyl--glycero-3-phospho-l-serine (DOPS) in atomistic detail. Contact maps between residues in the C domains with different lipid moieties support prior structural data describing how the C domains associate with membranes through electrostatic and hydrophobic interactions. Solvent-accessible surface area analysis quantified the extent to which residues in the C1 and C2 domains bury into the membrane. Calculations of the potential energy between the C domains and DOPC and DOPS revealed an FVIII membrane-binding orientation that agrees with previous experimental data. This study expands our knowledge of the structural basis of FVIII membrane association, which may be critical for the development of next-generation FVIII replacement constructs with improved activity.