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

Accurate solvation free energy ΔG_solv predictions require well parametrized force fields. In order to refit Lennard-Jones (LJ) parameters for improved ΔG_solv predictions for a variety of compound classes and chemical environments, a large number of ΔG_solv calculations is required. As the calculation of ΔG_solv 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 ΔG_solv 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 ΔG_solv is useful if the adaptation of LJ parameters is limited to atom types in the solute or if only ε is changed.