Towards a transferable nonelectrostatic model for continuum solvation: The electrostatic and nonelectrostatic energy correction model.

In this work, we introduce an electrostatic and non-electrostatic (ENE) correction to the solvation energy based on the Solvent-Accessible Surface Area (SASA) of the solute and the solvent static dielectric constant. The proposed correction was developed for neutral solutes in non-aqueous solvents, considering three different implicit solvation models based on a Self-Consistent Reaction Field treatment of solute-solvent mutual polarization using an Apparent Surface Charge formalism, namely the Integral Equation Formalism of the Polarizable Continuum Model using a continuous surface charge scheme (PCM), the Solvation Model based on solute electron density (SMD), and the generalized Finite-Difference Poisson-Boltzmann (FDPB) model. The proposed correction was parametrized on a diverse training set of 4980 solvation data from the Solv@tum database of experimental solvation energies, and validated on the non-aqueous subset of the MNSOL database comprising 2140 solvation energies. The performances of the proposed ENE models with minimal and extended parameters formulations have been analyzed and the latter variant has been further compared to the widely used Cavity, Dispersion, and Solvent structural effects (CDS) non-electrostatic model originally developed for the SMx family of implicit solvation models. Overall, a very good agreement between the computed solvation energies with the ENE correction and the reference experimental data has been found on both the training and test sets for all continuum solvation models considered. Furthermore, results for the ENE correction are on par with the reference CDS non-electrostatic model for both SMD and FDPB electrostatics, but with the advantage of using a lower number of parameters and thus an improved transferability between different electrostatics treatments.

Generalizing Continuum Solvation in Crystal to Nonaqueous Solvents: Implementation, Parametrization, and Application to Molecules and Surfaces.

We present an extension of a generalized finite-difference Poisson-Boltzmann (FDPB) continuum solvation model based on a self-consistent reaction field treatment to nonaqueous solvents. Implementation and reparametrization of the cavitation, dispersion, and structural (CDS) effects nonelectrostatic model are presented in CRYSTAL, with applications to both finite and infinite periodic systems. For neutral finite systems, computed errors with respect to available experimental data on free energies of solvation of 2523 solutes in 91 solvents, as well as 144 transfer energies from water to 14 organic solvents are on par with the reference SM12 solvation model for which the CDS parameters have been developed. Calculations performed on a TiO2 anatase surface and compared to VASPsol data revealed an overall very good agreement of computed solvation energies, surface energies, as well as band structure changes upon solvation in three different solvents, validating the general applicability of the reparametrized FDPB approach to neutral nonperiodic and periodic solutes in aqueous and nonaqueous solvents. For ionic species, while the reparametrized CDS model led to large errors on free energies of solvation of anions, addition of a corrective term based on Abraham's acidity of the solvent significantly improved the accuracy of the proposed continuum solvation model, leading to errors on aqueous pKa of a test set of 83 solutes divided by a factor of 4 compared to the reference solvation model based on density (SMD). Overall, therefore, these encouraging results demonstrate that the generalized FDPB continuum solvation model can be applied to a broad range of solutes in various solvents, ranging from finite neutral or charged solutes to extended periodic surfaces.

Analytical calculation of the solvent-accessible surface area and its nuclear gradients by stereographic projection: A general approach for molecules, polymers, nanotubes, helices, and surfaces.

In this article, we explore an alternative to the analytical Gauss-Bonnet approach for computing the solvent-accessible surface area (SASA) and its nuclear gradients. These two key quantities are required to evaluate the nonelectrostatic contribution to the solvation energy and its nuclear gradients in implicit solvation models. We extend a previously proposed analytical approach for finite systems based on the stereographic projection technique to infinite periodic systems such as polymers, nanotubes, helices, or surfaces and detail its implementation in the Crystal code. We provide the full derivation of the SASA nuclear gradients, and introduce an iterative perturbation scheme of the atomic coordinates to stabilize the gradients calculation for certain difficult symmetric systems. An excellent agreement of computed SASA with reference analytical values is found for finite systems, while the SASA size-extensivity is verified for infinite periodic systems. In addition, correctness of the analytical gradients is confirmed by the excellent agreement obtained with numerical gradients and by the translational invariance achieved, both for finite and infinite periodic systems. Overall therefore, the stereographic projection approach appears as a general, simple, and efficient technique to compute the key quantities required for the calculation of the nonelectrostatic contribution to the solvation energy and its nuclear gradients in implicit solvation models applicable to both finite and infinite periodic systems.

Imidazole in Aqueous Solution: Hydrogen Bond Interactions and Structural Reorganization with Concentration.

The structural and dynamic properties of imidazole in aqueous solution have been studied by means of classical and ab initio molecular dynamics simulations. We developed a new force field for the imidazole molecule with improved modeling of the electrostatic interactions, specifically tailored to address the well-known drawbacks of existing force fields based on the atomic fractional charge approach. To this end, we reparametrized the charge distribution on the heterocyclic ring, introducing an extra site accounting for the lone pair on the deprotonated nitrogen. The accuracy of the model in describing the hydrogen bond pattern in the aqueous solvent has been confirmed by comparing the classical results on imidazole-water interactions to accurate Car-Parrinello molecular dynamics simulations. It reproduces satisfactorily the experimental water/octanol partition coefficient of imidazole, as well as the structure of the imidazole molecular crystal. The force field has been finally applied to simulate aqueous solutions at various imidazole concentrations to obtain information on both imidazole-water and imidazole-imidazole interactions, providing a description of the different molecular arrangements in solution.

Assessment of GAFF2 and OPLS-AA General Force Fields in Combination with the Water Models TIP3P, SPCE, and OPC3 for the Solvation Free Energy of Druglike Organic Molecules.

Molecular dynamics simulations have been performed to compute the solvation free energy and the octanol/water partition coefficients for a challenging set of selected organic molecules, characterized by the simultaneous presence of functional groups coarsely spanning a large portion of the chemical space in druglike compounds and, in many cases, by a complex conformational landscape (2-propoxyethanol, acetylsalicylic acid, cyclohexanamine, dialifor, ketoprofen, nitralin, profluralin, terbacil). OPLS-AA and GAFF2 parametrizations of the organic molecules and of 1-octanol have been done via the Web-based automatic parameter generators, LigParGen [ Dodda et al. Nucl. Acids Res. 2017 , 121 , 3864 ] and PrimaDORAC [ Procacci J. Chem. Inf. Model. 2017 , 57 , 1240 ], respectively. For the water solvent, three popular three-point site models, TIP3P, SPCE, and OPC3, were tested. Solvation free energies in water and 1-octanol are evaluated using a recently developed nonequilibrium alchemical technology [ Procacci et al. J. Chem. Theory Comput. 2014 , 10 , 2813 ]. Extensive and accurate simulations, including all possible combinations of organic molecule, solvent, and solvent model, are allowed to assess the accuracy with regard to solvation free energies of the latest release of two widespread force fields, OPLS and GAFF. The collected data are relevant in the evaluation of the predictive power of these classical force fields (and of the related support software for automated parametrization) with regard to binding free energies in a drug-receptor system for industrial applications.