A COMPUTER MODELING STUDY OF THE INTERACTION BETWEEN TISSUE FACTOR PATHWAY INHIBITOR AND BLOOD-COAGULATION FACTOR XA

Activation of blood coagulation factor X to factor Xa (FXa) is inhibit ed by tissue factor pathway inhibitor (TFPI). The second Kunitz-type i nhibitory domain (K2) of TFPI binds a catalytic domain of FXa, whereas the first domain (K1) does not. We analyzed computer models of comple xes of FXa with K1 or K2, which were made using a crystal structure of FXa. Favorable hydrophobic interaction was observed in the complex of FXa with K2. Furthermore, we constructed a tertiary structure of FXa using CHIMERA to assess the accuracy of a homology modeling method. Th e isolated model structure of FXa agreed well with the crystal structu re, but analyses of complexes of this structure with K1 or K2 revealed that the models of complexes could not provide clear evidence of grea ter binding ability to K2 because of the positional difference of a fe w side chains interacting with the inhibitor.