Modeling human zymogen factor IX

Modern theoretical techniques are employed to provide complete three dimens ional structure for the zymogen and activated forms of human coagulation fa ctors IX and IXa. These structures are fully calcium bound and equilibrated in an electrically neutral aqueous environment. The relationship of struct ure to mutational data is examined. We find that a substantial relative ori entational change of the catalytic domain occurs on activation. Also, we fi nd that the electrostatistically dipolar nature of the catalytic domain is substantially modified upon activation, with cleavage of the negatively cha rged activation peptide leaving behind a largely hydrophobic face in factor IXa. While the backbone atoms of the catalytic residues have little relati ve movement, nearby loops are found that do move. The presence or absence o f these changes likely defines specificity.