Predicted solution structure of zymogen human coagulation FVII

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Abstract
A model solution structure for the complete tissue factor‐free calcium ion‐bound human zymogen FVII (residues 1–406) (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 X‐ray crystallographic structure of human coagulation FVIIa/TF complex bound with calcium ions (Banner et al., Nature 1996, 380, 41–46). 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 X‐ray 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 TF‐bound X‐ray crystal structure. An additional extension of the serine protease (SP) domain of the zymogen above a reference lipid surface by ∼7 Å was in agreement with experiment. Significant Gla‐EGF1 and EGF1‐EGF2 interdomain motions in the zymogen were observed. Carbohydrate dimers attached to Ser‐52 and Ser‐60 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 H‐bonded network while Lys‐341 occupies the S1 specific site in the zymogen. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 35–47, 2002