HOMOLOGY MODELING AND MOLECULAR-DYNAMICS SIMULATIONS OF THE GLA DOMAINS OF HUMAN COAGULATION-FACTOR-IX AND ITS G[12]A MUTANT

We have tested molecular dynamics as a predictive tool for stability o f protein structure. We first used the X-ray crystallographic coordina tes of bovine prothrombin fragment 1 to model the structure of the cia domain of human factor IX, an essential coagulation protein. In addit ion, a mutant protein that differs in only a single amino acid (G[12]A ) but is associated with one form of Hemophilia B was also modeled. Si mulations performed in an identical fashion for both proteins, with co nsiderable care to accommodate long-range forces in these highly ionic systems, indicated that substantial distortions occur in the mutant s tructure relative to the wild type factor IX. Surprisingly, the Gla do main (residues 1-34) of the wild type and mutant remain similar. Inste ad, it is the interaction of the added Ala at position 12 in the mutan t that repels the post-Gla region (residues >33, the C-terminal helix) region.