Development of an optimized parameter set for monovalent ions in the reference interaction site model of solvation

Abstract

Accurate modeling of aqueous monovalent ions is essential for understanding the function of biomolecules, such as nucleic acid stability and the binding of charged drugs to protein targets. The 1D and 3D reference interaction site models (1D- and 3D-RISM) of molecular solvation, as implemented in the AmberTools molecular modeling suite, are well suited for modeling mixtures of ionic species around biomolecules across a wide range of concentrations. However, the available ion model parameters were optimized for molecular dynamics simulations, not for the RISM framework, which includes a closure approximation. To address this, we optimized the Lennard-Jones 12–6 model for monovalent ions for 1D-RISM with the partial series expansion of order 3 closure by fitting to experimental values of ion–oxygen distance (IOD), hydration free energy (HFE), partial molar volume (PMV), and mean activity coefficient. The new parameter set demonstrated significant improvement in HFE, IOD, and mean activity coefficients, whereas no overall change was observed for the PMV. A second optimization step, introducing non-bonded fix (NBFIX) parameters into the model, was necessary to account for the cation–anion interactions that affect the mean activity coefficients. The new parameters were validated at finite salt concentrations against experimental data for 16 ion pairs and showed improved accuracy for 12 of them, with predictions for CsI and LiI ranked second best, while those for CsF and LiCl ranked third best among the tested parameter sets. The isothermal compressibilities for NaCl, KCl, and LiCl were compared against experimental data. Although 1D-RISM overestimated the value for pure water by ∼40%, the relative change as a function of salt concentration was improved with the new parameter set for NaCl and KCl. 1D-RISM results obtained with the new NaCl parameters were used to calculate the preferential interaction parameter of the ions around the 24L B-DNA using 3D-RISM. The new parameters demonstrated better agreement with the experiment at physiological and higher concentrations. At lower concentrations, the results primarily depended on the closure with little effect from the ion parameters. Overall, the ion parameters specifically developed for RISM show improved accuracy at infinite dilution and finite concentrations. No difference was observed for the preferential interaction parameters and isothermal compressibility calculations when comparing NBFIX and non-NBFIX parameters. However, the NBFIX parameters are numerically more stable at higher concentrations.