Abstract
A model solution structure for the complete tissue factorβfree calcium ionβbound human zymogen FVII (residues 1β406) (FVII) has been constructed to study possible conformational changes associated with the activation process and tissue factor (TF) binding. The initial structure for the present model was constructed using the Xβray crystallographic structure of human coagulation FVIIa/TF complex bound with calcium ions (Banner et al., Nature 1996, 380, 41β46). This model was subsequently subjected to lengthy molecular dynamics simulations. The Amber force field in conjunction with the PME electrostatic summation method was employed. The estimated TF free solution structure was then compared with the currently available Xβray crystal structures of FVIIa (with or without TF, variable inhibitor bound) to estimate the restructuring of FVII due to TF binding and activation. The solution structure of the zymogen FVII in the absence of TF is predicted to be an extended domain structure similar to that of the TFβbound Xβray crystal structure. An additional extension of the serine protease (SP) domain of the zymogen above a reference lipid surface by βΌ7 Γ
was in agreement with experiment. Significant GlaβEGF1 and EGF1βEGF2 interdomain motions in the zymogen were observed. Carbohydrate dimers attached to Serβ52 and Serβ60 did not cause restructuring in this domain. Minimal restructuring of the SP domain is found upon inference of the zymogen from the activated form. The catalytic triad residues maintain the Hβbonded network while Lysβ341 occupies the S1 specific site in the zymogen. Β© 2002 Wiley Periodicals, Inc. J Comput Chem 23: 35β47, 2002