Parameterization of the Hamiltonian Dielectric Solvent (HADES) reaction-field method for the solvation free energies of amino acid side-chain analogs

Abstract Optimization of the Hamiltonian dielectric solvent (HADES) method for biomolecular simulations in a dielectric continuum is presented with the goal of calculating accurate absolute solvation free energies while retaining the model's accuracy in predicting conformational free-energy differences. The solvation free energies of neutral and polar amino acid side-chain analogs calculated by using HADES, which may optionally include nonpolar contributions, were optimized against experimental data to reach a chemical accuracy of about 0.5 kcal mol^-1. The new parameters were evaluated for charged side-chain analogs. The HADES results were compared with explicit-solvent, generalized Born, Poisson-Boltzmann, and QM-based methods. The potentials of mean force (PMFs) between pairs of side-chain analogs obtained by using HADES and explicit-solvent simulations were used to evaluate the effects of the improved parameters optimized for solvation free energies on intermolecular potentials. Molecular dynamics and modeling: Parameterization of the recently developed Hamiltonian dielectric continuum solvation model (HADES) is refined to give the solvation free energies of amino-acid analogs within chemical accuracy. The figure shows the potential of mean force between two side-chain analogs immersed in a dielectric continuum.