title: Structural insights into the interaction of blood coagulation co-factor VIIIa with factor IXa: a computational protein-protein docking and molecular dynamics refinement study.
abstract: Coagulation factor X (FX) zymogen activation by factor IXa (FIXa) enzyme plays a critical role in the middle-phase of coagulation cascade. The activation process is catalytically inert and requires FIXa binding and complex formation with co-factor VIIIa (FVIIIa). In order to understand the structural details of the FVIIIa:FIXa complex, we employed knowledge-driven protein-protein docking and aqueous-phase MD refinement methods to develop a stable structural complex between FVIIIa and FIXa. The model shows that all four domains of FIXa wrap across FVIIIa that spans the co-factor binding surface of A2, A3 and C1 domains. The region surrounding the 558-helix of the A2-domain of FVIIIa is predicted to be the key interaction site with the helical segments of Lys293-Lys301 and Asp332-Arg338 residues of the serine-protease domain of FIXa. The hydrophobic helical stack between the GLA and EGF1 domains of FIXa is predicted to be primary interacting region with the A3-C2 domain interface of FVIIIa.
authors.affiliation: Department of Chemistry, North Carolina Agricultural and Technical State University, Greensboro, NC 27411, USA. Electronic address: divi@ncat.edu.
authors.forename: Divi
authors.initials: D
authors.lastname: Venkateswarlu
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D001665:Binding Sites; D001777:Blood Coagulation; D015949:Factor IXa / Q000737:chemistry*; D015944:Factor VIIIa / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D012996:Solutions; D055672:Static Electricity
chemical_list: D000596:Amino Acids; D012996:Solutions; D015944:Factor VIIIa; D015949:Factor IXa
keywords: Blood clotting; Factor IXa; Factor VIIIa; Molecular dynamics; Protein–protein docking; Tenase complex