Calculation of molecular free energies in classical potentials

Free energies of molecules can be calculated by quantum chemistry computations or by normal mode classical calculations. However, the first can be computationally impractical for large molecules and the second is based on the assumption of harmonic dynamics. We present a novel, accurate and complete calculation of molecular free energies in standard classical potentials. In this method we transform the molecule by relaxing potential terms which depend on the coordinates of a group of atoms in that molecule and calculate the free energy difference associated with the transformation. Then, since the transformed molecule can be treated as non-interacting systems, the free energy associated with these atoms is analytically or numerically calculated. This two-step calculation can be applied to calculate free energies of molecules or free energy difference between (possibly large) molecules in a general environment. We demonstrate the method in free energy calculations for methanethiol and butane molecules in vacuum and solvent. We suggest the potential application of free energy calculation of chemical reactions in classical molecular simulations.