| Abstract
| - Prediction of solvation free energies is an important subject in fundamental natural science but also importantto the pharmaceutical and food industry. A popular modeling approach is to treat the solution by an implicitsolvent model. The solute molecule is rigid with a fixed effective charge distribution localized at the atomicnuclei positions. The hydration free energy is described by the van der Waals energy, the solute cavity formationenergy in the water phase, and the change in electrostatic solute−solvent interaction energy. The dielectriccontinuum is generally assumed to be a simple medium, that is, linear, homogeneous, and isotropic. However,this approximation is quite severe and will give too hydrophilic solvation free energies. We show here thatthe simple medium approximation must be relaxed and nonlinearity must be taken into consideration. Instrong electric fields, the solvent polarization becomes saturated and the dielectric no longer responds linearlyin the applied field. This effect is well-described by the modified Langevin−Debye model. This nonlinearsolvation model is used to study the hydration of 181 small organic molecules. Atomic charges and radii ofthe solute molecule are described by a standard classical force field. We apply the optimized potentials forliquid simulation all atom (OPLS-AA) force field, which is parametrized to reproduce both structural andthermodynamical data. This leads to a mean unsigned error of 0.6 kcal/mol, which is a 25% improvementcompared to a simple medium approach. The nonlinear solvation model is further improved by introducinga few charge-scaling parameters for some functional groups that show a systematic deviation from theirexperimental data. This yields a mean unsigned error of 0.4 kcal/mol, which is only twice the experimentaluncertainty. Hence, we conclude that nonlinear dielectric effects are indeed important to incorporate in implicitsolvent models, even for neutral polar molecules.
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