Evaluation of solvation free energies for small molecules with the AMOEBA polarizable force field

Abstract

The effects of electronic polarization in biomolecular interactions will differ depending on the local dielectric constant of the environment, such as in solvent, DNA, proteins, and membranes. Here the performance of the AMOEBA polarizable force field is evaluated under nonaqueous conditions by calculating the solvation free energies of small molecules in four common organic solvents. Results are compared with experimental data and equivalent simulations performed with the GAFF pairwise-additive force field. Although AMOEBA results give mean errors close to "chemical accuracy," GAFF performs surprisingly well, with statistically significantly more accurate results than AMOEBA in some solvents. However, for both models, free energies calculated in chloroform show worst agreement to experiment and individual solutes are consistently poor performers, suggesting non-potential-specific errors also contribute to inaccuracy. Scope for the improvement of both potentials remains limited by the lack of high quality experimental data across multiple solvents, particularly those of high dielectric constant. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.

Keywords: fixed-charge force field; log P; molecular dynamics; polarizable force field; solvation free energies.

Figure 1

The structures of small molecules selected in this study. a) Dataset of small molecules for toluene, chloroform, acetonitrile and DMSO solvent. b) Dataset of additional small molecules for toluene and chloroform solvent.

Figure 2

Thermodynamic cycle37 adopted for calculating the solvation free energy of small molecules in four different nonaqueous solvents. The simulations involve three sets of calculations run in vacuum and in solvent (square box). Black circles represent a fully charged solute interacting with its environment, while the circle with no fill denotes a discharged and completely decoupled system. The gas phase intermolecular interactions (vdW decoupling) do not need to be evaluated because there is no interaction between the solute and the environment in vacuum.

Figure 3

AMOEBA (blue) and GAFF (black) calculated ΔG _solv for small molecules in toluene, chloroform, acetonitrile and DMSO against experimental ΔG _solv. Line of perfect agreement, y = x, shown as dashed line. Linear regression in each solvent plot gives the following equations: a) AMOEBA (y = 0.752 x − 0.4375), GAFF (y = 1.012 x + 0.153) b) AMOEBA (y = 0.571 x − 1.435), GAFF (y = 1.217 x + 1.722) c) AMOEBA (y = 1.169 x + 1.452), GAFF (y = 0.822 x − 0.813) and d) AMOEBA (y = 1.436 x + 2.986), GAFF (y = 1.164 x + 0.907). [Color figure can be viewed at wileyonlinelibrary.com]