Conformational Free Energy Changes via an Alchemical Path without Reaction Coordinates.

We introduce a novel method called restrain-free energy perturbation-release (R-FEP-R) to estimate conformational free energy changes via an alchemical path, which for some conformational landscapes like those associated with cellular signaling proteins in the kinase family is more direct and readily converged than the corresponding free energy changes along the physical path. The R-FEP-R method was developed from the dual topology free energy perturbation method that is widely applied to estimate the binding free energy difference between two ligands. In R-FEP-R, the free energy change between two conformational basins is calculated by free energy perturbations that remove those atoms involved in the conformational change from their initial conformational basin while simultaneously growing them back according to the final conformational basin. Both the initial and final dual topology states are unphysical, but they are designed in a way such that the unphysical contributions to the initial and final partition functions cancel. Compared with other advanced sampling algorithms such as umbrella sampling and metadynamics, the R-FEP-R method does not require predetermined transition pathways or reaction coordinates that connect the two conformational states. As a first illustration, the R-FEP-R method was applied to calculate the free energy change between conformational basins for alanine dipeptide in solution and for a side chain in the binding pocket of T4 lysozyme. The results obtained by R-FEP-R agree with the benchmarks very well.