Computational studies of human prothrombin fragment 1, the Gla domain of factor IX and several biological interesting mutants.

We have employed molecular dynamics simulations to understand the properties of the gamma-carboxyglutamic acid (Gla) domains of human prothrombin fragment 1 (residues 1-144) and factor IX (residues 1-47). The simulations are based on (1) the crystal structure of bovine prothrombin fragment 1 in the presence of calcium and (2) our subsequent simulation of the solution structure for which we found accommodation of the long range ionic forces critical. In addition, we have estimated the solution structures for key mutant proteins [prothrombin (Gla6 to Asp and Gla16 to Asp) and factor IX (Gly12 to Ala)]. The simulations for the latter two mutants do not stabilize, a result in concert with the known biological data.