Applicability of a thermodynamic cycle approach for a force field parametrization targeting non-aqueous solvation free energies.

Accurate solvation free energy ΔGsolv predictions require well parametrized force fields. In order to refit Lennard-Jones (LJ) parameters for improved ΔGsolv predictions for a variety of compound classes and chemical environments, a large number of ΔGsolv calculations is required. As the calculation of ΔGsolv is computational expensive, there is need for efficient but precise calculation methods. In this work, we focus on the computation of non-aqueous solvation free energies. We compare ΔGsolv results from highly precise reference simulations for transferring a solute from the vacuum into a condensed phase and results obtained from a thermodynamic cycle implementation. As test systems, we alter LJ parameters ε and σ of widely used GAFF atom types ca, cl, n1, oh and os in various solute/solvent combinations. We examine the degree of configurational space overlap and find an impact by hydrogen bonds and the solvent accessible surface area. We conclude that the application of a thermodynamic cycle for the parametrization of force fields targeting ΔGsolv is useful if the adaptation of LJ parameters is limited to atom types in the solute or if only ε is changed.