Molecular dynamics simulations studies on human coagulation factor Va

COMP 63

Tivadar Orban, Valentin Gogonea, and Michael Kalafatis. Department of Chemistry, Cleveland State University, Euclid Avenue at East 24th Street, Cleveland, OH 44115
Factor Va is the cofactor required for prothrombinase complex to achieve physiologically relevant rates for conversion of prothrombin to ?-thrombin. There are no structural informations on the cofactor. The current factor Va model based on its homology with ceruloplasmin lacks 46 amino acid residues from the carboxyl-terminal portion of the heavy chain (Arg664 to Arg709). We were not able to find any homologous peptide for the missing 46 amino acid residue sequence. Consequently, we used computer simulation techniques to obtain a three dimensional structure for this sequence. After insertion of the missing residues in the entire molecule, we allowed the cofactor to relax using molecular dynamic techniques. We have obtained a structure that allowed us to study the distance and location of the amino acids representing the factor Xa binding site, and those representing the prothrombin binding site. Those are key residues regulating the formation of prothrombinase complex. A detailed presentation of the structure is provided.