New Interaction Parameters for Charged Amino Acid Side Chains in the GROMOS Force Field.

Abstract

A GROMOS force-field parameter set 54A8 is developed, which is based on the latest 54A7 set [Schmid et al. Eur. Biophys. J. 2011, 40, 843–856] and involves a recalibration of the nonbonded interaction parameters for the charged amino acid side chains, based on ionic side chain analogs. After a thorough analysis of the available experimental data, conventional hydration free energies for the ammonium; mono-, di-, tri-, and tetramethyl-ammonium; formate; acetate; propanoate; imidazolium; and guanidinium ions are combined with a standard absolute intrinsic proton hydration free energy ΔGhyd⊖[Hg+] = −1100 kJ·mol–1 to yield absolute intrinsic single-ion hydration free energies serving as experimental target data. The raw hydration free energies calculated from atomistic simulations are affected by electrostatic and finite-size artifacts, and corrections are applied to reach methodological independence prior to comparison with these experimental values. Except for monomethyl-ammonium, ions with parameters derived directly from the 54A7 force field considerably underestimate (ammonium, formate, acetate, propanoate, guanidinium) or overestimate (di-, tri-, and tetramethyl-ammonium; imidazolium) the magnitude of the intrinsic hydration free energy, the largest deviation affecting the acetate ion (40.0 kJ·mol–1). After reparameterization into 54A8, the mean and maximal absolute deviations between simulated and experimental data over the set of 10 ions are reduced from 23.1 and 40.0 kJ·mol–1, respectively, to 1.8 and 6.3 kJ·mol–1, respectively. Although the 54A7 and 54A8 parameter sets differ significantly in terms of the hydration free energies of the ions considered, other properties such as ion–water radial distribution functions and ion–ion potentials of mean force appear to be only moderately sensitive to this change. These properties are similar for the two sets and, in the case of the ion–water radial distribution functions, in good agreement with available experimental data.