Y. Zenmei Ohkubo, James H. Morrissey, and Emad Tajkhorshid.
Dynamical view of membrane binding and complex formation of human
factor VIIa and tissue factor.
Journal of Thrombosis and Haemostasis, 8:1044-1053, 2010.
(PMC: PMC2890040)
OHKU2010-ET
Background: Themolecularmechanismof enhancement of the enzymatic activity of factor
VIIa by tissue factor (TF) is not fully understood, primarily because of the lack of atomic
models for themembrane-bound form of the TF–FVIIa complex. Objectives: To construct
the first membrane-bound model of the TF–FVIIa complex, and to investigate the
dynamics of the complex in solution and on the surface of anionic membranes by using
large-scale molecular dynamics (MD) simulations in full atomic detail. Methods: Membrane
bound models of the TF–FVIIa complex and the individual factors were constructed and
subjected to MD simulations, in order to characterize protein–protein and protein–lipid
interactions, and to investigate the dynamics of TF and FVIIa. Results: The MD trajectories
reveal that isolated FVIIa undergoes large structural fluctuation, primarily due to the
hingemotions between its domains,whereas solubleTF(sTF) is structurally stable. Upon
complex formation, sTF restricts the motion of FVIIa significantly. The results also show
that, in the membrane-bound form, sTF directly interacts with the lipid headgroups, even
in the absence of FVIIa. Conclusion: The first atomic models of membrane-bound sTF–
FVIIa, FVIIa and sTF are presented, revealing that sTFforms direct contacts with the lipids,
both in the isolated form and in complex with FVIIa. The main effect of sTF binding to
FVIIa is spatial stabilization of the catalytic site of FVIIa, which ensures optimal interaction
with the substrate, FX.
