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A Polarization-Consistent Model for Alcohols to Predict Solvation Free Energies.

ABSTRACT: Classical nonpolarizable models, normally based on a combination of Lennard-Jones sites and point charges, are extensively used to model thermodynamic properties of fluids, including solvation. An important shortcoming of these models is that they do not explicitly account for polarization effects, i.e., a description of how the electron density responds to changes in the molecular environment. Instead, polarization is implicitly included, in a mean-field sense, into the parameters of the model, usually by fitting to pure liquid properties (e.g., density). This causes problems when trying to describe thermodynamic properties that involve a change of phase (e.g., enthalpy of vaporization), that directly depend on the electronic response of the medium (e.g., dielectric constant), and that require mixing or solvation in different media (e.g., solvation free energies). Fully polarizable models present a natural route for addressing these limitations but at the price of a much higher computational cost. In this work, we combine the best of those two approaches by running fast simulations using nonpolarizable models and applying post facto corrections to the computed properties in order to account for the effects of polarization. By applying this new paradigm, a new united-atom force field for alcohols is developed that is able to predict both pure liquid properties, including dielectric constant, and solvation free energies in different solvents with a high degree of accuracy. This paves the way for the development of a generic classical nonpolarizable force field that can predict solvation of drug-like molecules in a variety of solvents.

SUBMITTER: Barrera MC

PROVIDER: S-EPMC7145284 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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A Polarization-Consistent Model for Alcohols to Predict Solvation Free Energies.

Barrera Maria Cecilia MC Jorge Miguel M

Journal of chemical information and modeling 20200203 3

Classical nonpolarizable models, normally based on a combination of Lennard-Jones sites and point charges, are extensively used to model thermodynamic properties of fluids, including solvation. An important shortcoming of these models is that they do not explicitly account for polarization effects, i.e., a description of how the electron density responds to changes in the molecular environment. Instead, polarization is implicitly included, in a mean-field sense, into the parameters of the model, ...[more]

PMID: 31977210

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Project description:Accurate yet efficient computational models of solvent environment are central for most calculations that rely on atomistic modeling, such as prediction of protein-ligand binding affinities. In this study, we evaluate the accuracy of a recently developed generalized Born implicit solvent model, GBNSR6 (Aguilar et al. J. Chem. Theory Comput. 2010, 6, 3613-3639), in estimating the electrostatic solvation free energies (?G(pol)) and binding free energies (??G(pol)) for small protein-ligand complexes. We also compare estimates based on three different explicit solvent models (TIP3P, TIP4PEw, and OPC). The two main findings are as follows. First, the deviation (RMSD = 7.04 kcal/mol) of GBNSR6 binding affinities from commonly used TIP3P reference values is comparable to the deviations between explicit models themselves, e.g. TIP4PEw vs TIP3P (RMSD = 5.30 kcal/mol). A simple uniform adjustment of the atomic radii by a single scaling factor reduces the RMS deviation of GBNSR6 from TIP3P to within the above "error margin" - differences between ??G(pol) estimated by different common explicit solvent models. The simple radii scaling virtually eliminates the systematic deviation (??G(pol)) between GBNSR6 and two out of the three explicit water models and significantly reduces the deviation from the third explicit model. Second, the differences between electrostatic binding energy estimates from different explicit models is disturbingly large; for example, the deviation between TIP4PEw and TIP3P estimates of ??G(pol) values can be up to ?50% or ?9 kcal/mol, which is significantly larger than the "chemical accuracy" goal of ?1 kcal/mol. The absolute ?G(pol) calculated with different explicit models could differ by tens of kcal/mol. These discrepancies point to unacceptably high sensitivity of binding affinity estimates to the choice of common explicit water models. The absence of a clear "gold standard" among these models strengthens the case for the use of accurate implicit solvation models for binding energetics, which may be orders of magnitude faster.

Dataset Information

A Polarization-Consistent Model for Alcohols to Predict Solvation Free Energies.

Publications

A Polarization-Consistent Model for Alcohols to Predict Solvation Free Energies.

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