Modeling zymogen protein C

A solution structure for the complete zymogen form of human coagulation pro tein C is modeled. The initial core structure is based on the x-ray crystal lographic structure of the gamma -carboxyglutamic acid (Gla)-domainless act ivated form. The Gla domain (residues 1-48) is modeled from the x-ray cryst al coordinates of the factor VIIa/tissue factor complex and oriented with t he epidermal growth factor-1 domain to yield an initial orientation consist ent with the x-ray crystal structure of porcine factor IXa. The missing C-t erminal residues in the light chain (residues 147-157) and the activation p eptide residues 158-169 were introduced using homology modeling so that the activation peptide residues directly interact with the residues in the cal cium binding loop. Molecular dynamics simulations (Amber-particle-mesh-Ewal d) are used to obtain the complete calcium-complexed solution structure. Th e individual domain structures of protein C in solution are largely unaffec ted by solvation, whereas the Gla-epidermal growth factor-1 orientation evo lves to a form different from both factors VIIa and IXa. The solution struc ture of the zymogen protein C is compared with the crystal structures of th e existing zymogen serine proteases: chymotrypsinogen, proproteinase, and p rethrombin-2. Calculated electrostatic potential surfaces support the invol vement of the serine protease calcium ion binding loop in providing a suita ble electrostatic environment around the scissile bond for IIa/thrombomodul in interaction.