The effect of different treatments of the nonbonded interactions in simulations employing the recently introduced GROMOS-compatible 2016H66 force field is evaluated based on calculations carried out with the GROMACS software. This is done considering four thermodynamic and transport properties (pure liquid density, vaporization enthalpy, surface-tension coefficient, and self-diffusion constant) of 58 organic liquids representative of the chemical groups alcohol, ether, aldehyde, ketone, carboxylic acid, ester, amine, amide, thiol, sulfide, disulfide, and aromatic compounds, also including water (SPC model). A dipalmitoylphosphatidylcholine bilayer system is considered as well. The simulated properties are found to be very sensitive to the treatment of the long-range dispersion interactions, notably for the least polar systems. In general, the treatment of the long-range electrostatic or Lennard-Jones interactions using homogeneous correction terms or lattice-sum approaches yield similar results, with punctual discrepancies. The combination of a lattice-sum approach for the electrostatic interactions with a straight-cutoff truncation of the Lennard-Jones interactions at a distance of at least 1.2 nm is found to represent a good compromise setup within GROMACS for achieving compatibility with the reference results obtained using GROMOS as well as a comparable level of agreement with the experimental data. This study also reveals two potential issues with the GROMACS software, related to an incorrect calculation of the pressure when using LINCS in version 4.0.7 and an inadequate implementation of the twin-range scheme in version 5.1.2.

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The calibration of torsional interaction terms by fitting relative gas-phase conformational energies against their quantum-mechanical values is a common procedure in force-field development. However, much less attention has been paid to the optimization of third-neighbor nonbonded interaction parameters, despite their strong coupling with the torsions. This article introduces an algorithm termed LLS-SC, aimed at simultaneously parametrizing torsional and third-neighbor interaction terms based on relative conformational energies. It relies on a self-consistent (SC) procedure where each iteration involves a linear least-squares (LLS) regression followed by a geometry optimization of the reference structures. As a proof-of-principle, this method is applied to obtain torsional and third-neighbor interaction parameters for aliphatic chains in the context of the GROMOS 53A6 united-atom force field. The optimized parameter set is compared to the original one, which has been fitted manually against thermodynamic properties for small linear alkanes. The LLS-SC implementation is freely available under http://github.com/mssm-labmmol/profiler.

The level of accuracy that can be achieved by a force field is influenced by choices made in the interaction-function representation and in the relevant simulation parameters. These choices, referred to here as functional-form variants (FFVs), include for example the model resolution, the charge-derivation procedure, the van der Waals combination rules, the cutoff distance, and the treatment of the long-range interactions. Ideally, assessing the effect of a given FFV on the intrinsic accuracy of the force-field representation requires that only the specific FFV is changed and that this change is performed at an optimal level of parametrization, a requirement that may prove extremely challenging to achieve in practice. Here, we present a first attempt at such a comparison for one specific FFV, namely the choice of a united-atom (UA) versus an all-atom (AA) resolution in a force field for saturated acyclic (halo)­alkanes. Two force-field versions (UA vs AA) are optimized in an automated way using the CombiFF approach against 961 experimental values for the pure-liquid densities ρliq and vaporization enthalpies ΔH vap of 591 compounds. For the AA force field, the torsional and third-neighbor Lennard–Jones parameters are also refined based on quantum-mechanical rotational-energy profiles. The comparison between the UA and AA resolutions is also extended to properties that have not been included as parameterization targets, namely the surface-tension coefficient γ, the isothermal compressibility κ T , the isobaric thermal-expansion coefficient α P , the isobaric heat capacity c P , the static relative dielectric permittivity ϵ, the self-diffusion coefficient D, the shear viscosity η, the hydration free energy ΔG wat, and the free energy of solvation ΔG che in cyclohexane. For the target properties ρliq and ΔH vap, the UA and AA resolutions reach very similar levels of accuracy after optimization. For the nine other properties, the AA representation leads to more accurate results in terms of η; comparably accurate results in terms of γ, κ T , α P , ϵ, D, and ΔG che; and less accurate results in terms of c P and ΔG wat. This work also represents a first step toward the calibration of a GROMOS-compatible force field at the AA resolution.