Publications

Almlöf M, Carlsson J, Åqvist J

J. Chem. Theory Comput. **3** (6) 2162-2175
[2007-11-00; online 2007-11-01]

A linear response method for estimating the free energy of solvation is presented and validated using explicit solvent molecular dynamics, thermodynamic perturbation calculations, and experimental data. The electrostatic contribution to the solvation free energy is calculated using a linear response estimate, which is obtained by comparison to the free energy calculated using thermodynamic perturbation. Systematic deviations from the value of (1)/2 in the potential energy scaling factor are observed for some types of compounds, and these are taken into account by introducing specific coefficients for different chemical groups. The derived model reduces the rms error of the linear response estimate significantly from 1.6 to 0.3 kcal/mol on a training set of 221 molecules used to parametrize the model and from 3.7 to 1.3 kcal/mol on a test set of 355 molecules that were not used in the derivation of the model. The total solvation free energy is estimated by combining the derived model with an empirical size dependent term for predicting the nonpolar contribution. Using this model, the experimental hydration free energies for 192 molecules are reproduced with an rms error of 1.1 kcal/mol. The use of LIE in simplified binding free energy calculations to predict protein-ligand binding free energies is also discussed.

PubMed 26636209

DOI 10.1021/ct700106b

Crossref 10.1021/ct700106b