A free-energy perturbation method based on Monte Carlo simulations using quantum mechanical calculations (QM/MC/FEP method): application to highly solvent-dependent reactions.

This study describes the framework of the quantum mechanical (QM)/Monte Carlo (MC)/free-energy perturbation (FEP) method, a FEP method based on MC simulations using quantum chemical calculations. Because a series of structures generated by interpolating internal coordinates between transition state and reactant did not produce smooth free-energy profiles, we used structures from the intrinsic reaction coordinate calculations. This method was first applied to the Diels-Alder reaction between methyl vinyl ketone and cyclopentadiene and produced ΔG( sol)‡ values of 20.