ES/IS: Estimation of conformational free energy by combining dynamics simulations with explicit solvent with an implicit solvent continuum model

This paper reviews a recently developed method for calculating the total co nformational free energy of a solute macromolecule in water solvent. The me thod consists of a relatively short simulation by molecular dynamics with e xplicit solvent molecules (ES) to produce a set of microstates of the macro scopic conformation. Conformational internal solute energy and entropy are obtained from the simulation, the latter in the quasi-harmonic approximatio n by analysis of the covariance matrix. The implicit solvent (IS) surface e nergy-dielectric continuum model is used to calculate the average solvation free energy as the sum of the free energies of creating the solute-size hy drophobic cavity, of the van der Waals solute-solvent interactions and of t he polarization of water solvent by the solute's charges. We have earlier a pplied this method to calculate the conformational free energy of native an d intentionally misfolded globular conformations of proteins (the EMBL set of deliberately misfolded proteins), and have obtained good discrimination in favor of the native conformations in all instances. These results are su mmarized and further analyzed to show that, on average, three major compone nt terms of the free energy all contribute in favor of discrimination. We d iscuss possible improvements of the ES/IS method. It is shown how the force field can be made self-consistent by adapting the parameters for calculati on of surface and polarization free energies closely to the molecular mecha nics force field used in the dynamics simulation, using established simulat ion methods to compute free energies for cavity formation and a charging pr ocess with the molecular mechanics force field to provide a set of (quasi-e xperimental) reference data that can be used to refine the parameters of th e continuum models. The molecular surface area together with a microscopic surface free energy near 70 cal/(mol Angstrom(2)) is found to be a consiste nt descriptor of the cavity free energy. Preliminary results indicate that a linear-response approximation for the polarization of water solvent react ion near typical polar and charged protein groups is accurate to within app roximately 90%. (C) 1999 Elsevier Science B.V. All rights reserved.