Molecular Modelling of Ionic Liquids: Force-Field Validation and Thermodynamic Perspective from Large-Scale Fast-Growth Solvation Free Energy Calculations

Molecular simulations are becoming a common tool for the investigation of dynamic and thermodynamic properties of novel solvents such as ionic liquids and the more recent deep eutectic solvents. As the electrostatics derived from ab initio calculations often fail to reproduce the experimental behaviors of these functionalized solvents, a common treatment is scaling the atomic charges to improve the accord between experimental and computational results for some selected properties, e.g., the density of the liquids. Although there are many computational benchmarks on structural properties of bulk ionic liquids, the choice of the best scaling parameter remains an open question. As these liquids are designed to solvate solutes, whether the solvation thermodynamics could be correctly described is of utmost importance in practical situations. Therefore, in the current work, we provide a thermodynamic perspective of this charge scaling issue directly from solute-solvent interactions. We present a comprehensive large-scale calculation of solvation free energies via nonequilibrium fast-switching simulations for a spectrum of molecules in ionic liquids, the atomic charges of which derived from ab initio calculations are scaled to find the best scaling factor that maximizes the prediction-experiment correlation. The density-derived choice of the scaling parameter as the estimate from bulk properties is compared with the solvation-free-energy-derived one. We observed that when the scaling factor is decreased from 1.0 to 0.5, the mass density exhibits a monotonically decreasing behavior, which is caused by weaker inter-molecular interactions produced by the scaled atomic charges. However, the solvation free energies of external agents do not show consistent monotonic behaviors like the bulk property, the underlying physics of which are elucidated to be the competing electrostatic and vdW responses to the scaling-parameter variation. More intriguingly, although the recommended value for charge scaling from bulk properties falls in the neighborhood of 0.6~0.7, solvation free energies calculated at this value are not in good agreement with the experimental reference. By modestly increasing the scaling parameter (e.g., by 0.1) to avoid over-scaling of atomic charges, the solute-solvent interaction free energy approaches the reference value and the quality of calculated solvation thermodynamics approaches the hydration case. According to this phenomenon, we propose a feasible way to obtain the best scaling parameter that produces balanced solute-solvent and solvent-solvent interactions, i.e., first scanning the density-scaling-factor profile and then adding ~0.1 to that solution. We further calculate the partition coefficient or transfer free energy of solutes from water to ionic liquids to provide another thermodynamic perspective of the charge scaling benchmark. Another central result of the current work is about the widely used force fields to describe bonded and vdW terms for ionic liquids derivatives. These pre-fitted transferable parameters are evaluated and refitted in a system-specific manner to provide a detailed assessment of the reliability and accuracy of these commonly used parameters. Component-specific refitting procedures unveil that the bond-stretching term is the most problematic part of the GAFF derivatives and the angle-bending term in some cases is also not accurate enough. Astonishingly, the torsional potential defined in these pre-fitted force fields performs extremely well.