Abstract
Hydration free energy (HFE) calculations are often used to assess the performance of biomolecular force fields and the quality of assigned parameters. The AMOEBA polarizable force field moves beyond traditional pairwise additive models of electrostatics and may be expected to improve upon predictions of thermodynamic quantities such as HFEs over and above fixed-point-charge models. The recent SAMPL4 challenge evaluated the AMOEBA polarizable force field in this regard but showed substantially worse results than those using the fixed-point-charge GAFF model. Starting with a set of automatically generated AMOEBA parameters for the SAMPL4 data set, we evaluate the cumulative effects of a series of incremental improvements in parametrization protocol, including both solute and solvent model changes. Ultimately, the optimized AMOEBA parameters give a set of results that are not statistically significantly different from those of GAFF in terms of signed and unsigned error metrics. This allows us to propose a number of guidelines for new molecule parameter derivation with AMOEBA, which we expect to have benefits for a range of biomolecular simulation applications such as protein-ligand binding studies.
Highlights
Hydration free energy (HFE) calculations have long been used as a tool for validating the accuracy of molecular mechanical force fields and comparing performance between different theoretical approaches.[1−4] The widespread use of hydration free energies in force field development can be primarily rationalized with two main arguments: first, the speed of equilibration and sampling for small water-solute systems allows HFEs to be rapidly estimated with high precision and used as fair comparisons between methodologies, and second, accurate HFE predictions have a direct relevance to the correct prediction of other experimental metrics such as protein−ligand binding free energies.[2,5,6]
Multipole parameters are derived from a geometry-optimized QM structure via a distributed multipole analysis (DMA)[48,49] and further fitted to recreate the molecular electrostatic potential (ESP) calculated with a larger QM basis set. van der Waals and valence parameters are assigned based on similarity to existing atom types
The performance of the AMOEBA force field in the SAMPL4 HFE challenge indicated that improvements were likely possible in the parametrization process
Summary
Hydration free energy (HFE) calculations have long been used as a tool for validating the accuracy of molecular mechanical force fields and comparing performance between different theoretical approaches.[1−4] The widespread use of hydration free energies in force field development can be primarily rationalized with two main arguments: first, the speed of equilibration and sampling for small water-solute systems allows HFEs to be rapidly estimated with high precision and used as fair comparisons between methodologies, and second, accurate HFE predictions have a direct relevance to the correct prediction of other experimental metrics such as protein−ligand binding free energies.[2,5,6]Despite the utility of HFE data for computational method development, the majority of solutes for which experimental data exist are small, fragment-like compounds that may have little relevance to the larger drug-like molecules of interest in many biomolecular simulations.[7−9] Validating force field transferability with HFE estimates ideally requires a broad evaluation of performance across a range of chemical functionalities and sizes. There remains a great deal of interest in the development and application of polarizable force fields in this regard.[16−20] By incorporating an explicit representation of polarization into the underlying energy function, polarizable force fields are able to inherently respond to environmental changes dynamically during simulations, in addition to better capturing subtleties in molecular interactions. This response to environment changes should enhance the transferability and accuracy of such force fields and reduce the need for empirical reparametrization compared to traditional pairwise additive models. HFE calculations have repeatedly been used as a challenge in the development of a variety of polarizable force fields, often showing good agreement with experiment for small organic molecules.[21−23]
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