Implicit solvent models: Combining an analytical formulation of continuum electrostatics with simple models of the hydrophobic effect

The recent development of approximate analytical formulations of continuum electrostatics opens the possibility of efficient and accurate implicit sol vent models for biomolecular simulations. One such formulation (ACE, Schaef er & Karplus, J. Phys. Chem., 1996, 100:1578) is used to compute the electr ostatic contribution to solvation and conformational free energies of a set of small solutes and three proteins. Results are compared to finite-differ ence solutions of the Poisson equation (FDPB) and explicit solvent simulati ons and experimental data where available. Small molecule solvation free en ergies agree with FDPB within 1-1.5 kcal/mol, which is comparable to differ ences in FDPB due to different surface treatments or different force field parameterizations. Side chain conformation free energies of aspartate and a sparagine are in qualitative agreement with explicit solvent simulations, w hile 74 conformations of a surface loop in the protein Ras are accurately r anked compared to FDPB. Preliminary results for solvation free energies of small alkane and polar solutes suggest that a recent Gaussian model could b e used in combination with analytical continuum electrostatics to treat non polar interactions. (C) 1999 John Wiley & Sons, Inc.