A Proposed Solution Structural Model for Human Coagulation Tenase Complex between Factor VIIIa and IXa: A Protein-Protein Docking and MD Refinement Study

Abstract

Activation of blood coagulation factor X to Xa plays central role in the clotting cascade. The protein-protein complex between the co-factor VIIIa and the proteolytic enzyme IXa is involved in the activation of X in the intrinsic coagulation pathway. Despite a large body of experimental data in understanding the specific protein-protein interaction sites within the tenase complex as well as the structure-function relationship between the tenase complex and X/Xa, the precise atomic level understanding of these interactions is not well understood, essentially due to lack of experimental X-ray crystal structure for the complex. In this presentation, we propose a solution structure for the complex between the activated co-factor VIIIa (a 1383 residue length five-domain protein) and the activating enzyme IXa (a 379 residue length four-domain protein). A systematic protein-protein docking approach was employed to generate a pool of 50 best docking poses between fVIIIa and fIXa. The starting structures for fVIIIa and fIXa were derived from explicit-solvent MD simulations of several hundred nanoseconds. A consensus structural complex (fVIIIa:fIXa) was identified that satisfied several possible distance constraints within the complex as well as existing genetic and experimental mutagenesis data. The docked complex was further refined for 150ns of MD refinement in explicit water to obtain a stable solution structure. The specific inter- and intra-domain interactions between the co-factor VIIIa and the enzyme IXa will be discussed.