Abstract
We test a hypothesis that the closed form of the C2 domain of coagulation factor V is more stable than the open form in an aqueous environment using a two-dimensional free-energy calculation with a simple dielectric solvent model. Our result shows that while the free-energy difference between two forms is small, favoring the closed form, a two-dimensional free-energy surface (FES) reveals that a transition state (1.53 kcal/mol) exists between the two conformations. By mapping the one-dimensional order parameter DeltaQ onto the two-dimensional FES, we search the conformational change path with the highest Boltzmann weighting factor between the closed and open form of the factor V C2 domain. The predicted transition path from the closed to open form is not that of simple side chain movements, but instead concerted movements of several loops. We also present a one-dimensional free-energy profile using a collective order parameter, which in a coarse manner locates the energy barriers found on the two-dimensional FES.