Gregory D. Hawkins

Pairwise solute descreening of solute charges from a dielectric medium

Abstract We present an algorithm for incorporating a pairwise descreening approximation into the calculation of the electrostatic component of the polarization free energy of solvation within the generalized Born approximation. The method was tested on a set of 139 molecules containing H, C, O, and N. The complexity of the descreening calculation is greatly simplified by the pairwise approximation; nevertheless, using the pairwise descreening method to parameterize a new version of a previous generalized Born solvation model, we found that the rms error relative to experiment increased by only 0.2 kcal/mol.

IMPROVED METHODS FOR SEMIEMPIRICAL SOLVATION MODELS

We present improved algorithms for the SMx (x = 1, 1a, 2, 3) solvation models presented previously [see the overview in C. J. Cramer and D. G. Truhlar, J. Comp.‐Aided Mol. Design, 6, 629 (1992)]. These models estimate the free energy of solvation by augmenting a semiempirical Hartree‐Fock calculation on the solute with the generalized Born (GB) model for electric polarization of the solvent and a surface tension term based on solvent‐accessible surface area. This article presents three improvements in the algorithms used to carry out such calculations, namely (1) an analytical accessible surface area algorithm, (2) a more efficient radial integration scheme for the dielectric screening computation in the GB model, and (3) a damping algorithm for updating the GB contribution to the Fock update during the iterations to achieve a self‐consistent field. Improvements (1) and (2) decrease the computer time, and improvement (3) leads to more stable convergence. Improvement (2) removes a small systematic numerical error that was explicitly absorbed into the parameterization in the SMx models. Therefore, we have adjusted the parameters for one of the previous models to yield essentially identical performance as was obtained originally while simultaneously taking advantage of improvement (2). The resulting model is called SM2.1. The fact that we obtain similar results after removing the systematic quadrature bias attests to the robustness of the original parameterization.

Density functional solvation model based on CM2 atomic charges

We extend the SM5 solvation model for calculating solvation free energies of a variety of organic solutes in both aqueous and organic solvents so that it can be employed in conjunction with high-level electronic structure calculations. The extension is illustrated by presenting three implementations based on density-functional theory (DFT). The three implementations are called SM5.42R/BPW91/MIDI!6D, SM5.42R/BPW91/DZVP, and SM5.42R/BPW91/6-31G*. They have the following features: (1) They utilize gradient-corrected DFT with polarized double zeta basis sets to describe the electronic structure of a solute. The particular exchange-correlation functional adopted is Becke’s exchange with the Perdew–Wang 1991 correlation functional, usually called BPW91. The MIDI!6D, DZVP, and 6-31G* basis sets are used. (2) They employ fixed solute geometries in solvation calculations. The model is designed to predict solvation free energies based on any reasonably accurate gas-phase solute geometry. (3) The electric polarizati...

Universal reaction field model based on ab initio Hartree–Fock theory

Abstract We present a model for free energies of solvation based on Hartree–Fock self-consistent-reaction-field (SCRF) calculations for electrostatics combined with atomic surface tensions (AST) for deviations from bulk electrostatics in the first solvation shell, including cavity, dispersion, and solvent-structure contributions. The SCRF part combines an ab initio treatment of the solute with solute–solvent interactions modeled using class IV charges. The AST part is parameterized for both water and general organic solvents. Mean unsigned errors are 3.9 kcal/mol for 49 ions in water and 0.46 kcal/mol for 275 neutrals in 91 solvents.

Universal Solvation Model Based on Conductor-Like Screening Model

Atomic surface tensions are parameterized for use with solvation models in which the electrostatic part of the calculation is based on the conductor‐like screening model (COSMO) and the semiempirical molecular orbital methods AM1, PM3, and MNDO/d. The convergence of the calculated polarization free energies with respect to the numerical parameters of the electrostatic calculations is first examined. The accuracy and precision of the calculated values are improved significantly by adjusting two parameters that control the segmentation of the solvent‐accessible surface that is used for the calculations. The accuracy of COSMO calculations is further improved by adopting an optimized set of empirical electrostatic atomic radii. Finally, the electrostatic calculation is combined with SM5‐type atomic surface tension functionals that are used to compute the nonelectrostatic portions of the solvation free energy. All parameterizations are carried out using rigid (R) gas‐phase geometries; this combination (SM5‐type surface tensions, COSMO electrostatics, and rigid geometries) is called SM5CR. Six air–water and 76 water–solvent partition coefficients are added to the training set of air–solvent data points previously used to parameterize the SM5 suite of solvation models, thereby bringing the total number of data points in the training set to 2266. The model yields free energies of solvation and transfer with mean unsigned errors of 0.63, 0.59, and 0.61 kcal/mol for AM1, PM3, and MNDO/d, respectively, over all 2217 data points for neutral solutes in the training set and mean unsigned errors of 3.0, 2.7, and 3.1 kcal/mol, respectively, for 49 data points for the ions.

Modeling The Effect of Solvation on Structure, Reactivity, and Partitioning of Organic Solutes: Utility in Drug Design

The SMx family of quantum mechanical solvation models accounts for electric and electronic polarization via the generalized Born model and for non-electrostatic components of solvation by microscopic surface tensions. The SM5.4 model, which is the most physical member of the SMx family, has been parameterized using two electronic Hamiltonians, AM1 and PM3. For both Hamiltonians, solvation parameters are obtained for water and for any organic solvent for which certain macroscopic data are available, in particular, the index of refraction, bulk surface tension, dielectric constant, and hydrogen bonding acidity and basicity as measured by the Abraham empirical α 2 H and β 2 H scales. For neutral solutes, the mean unsigned errors for aqueous and non-aqueous free energies of solvation are both 0.5 kcal / mol based on 215 and 1786 data points, respectively (for either Hamiltonian). By adding solvation effects to the gas-phase Hamiltonian, it is possible to model the effects of solvent on conformational analysis, molecular recognition, reaction kinetics, etc. The SM5.4 model is also useful for the calculation of solute partitioning between two solvents. Moreover, it is possible to generalize the SM5.4 model to media that are less well characterized than homogeneous solvents—an example is presented here for the case of bilayers of phosphatidyl choline—in order to model partitioning between biophases.