ES/IS: estimation of conformational free energy by combining dynamics simulations with explicit solvent with an...

This paper reviews a recently developed method for calculating the total conformational free energy of a solute macromolecule in water solvent. The method consists of a relatively short simulation by molecular dynamics with explicit solvent molecules (ES) to produce a set of microstates of the macroscopic conformation. Conformational internal solute energy and entropy are obtained from the simulation, the latter in the quasi-harmonic approximation by analysis of the covariance matrix. The implicit solvent (IS) surface energy-dielectric continuum model is used to calculate the average solvation free energy as the sum of the free energies of creating the solute-size hydrophobic cavity, of the van der Waals solute-solvent interactions and of the polarization of water solvent by the solute's charges. We have earlier applied this method to calculate the conformational free energy of native and 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 summarized and further analyzed to show that, on average, three major component terms of the free energy all contribute in favor of discrimination. We discuss possible improvements of the ES/IS method. It is shown how the force field can be made self-consistent by adapting the parameters for calculation of surface and polarization free energies closely to the molecular mechanics force field used in the dynamics simulation, using established simulation methods to compute free energies for cavity formation and a charging process with the molecular mechanics force field to provide a set of (quasi-experimental) reference data that can be used to refine the parameters of the continuum models. The molecular surface area together with a microscopic surface free energy near 70 cal/(mol A2) is found to be a consistent descriptor of the cavity free energy. Preliminary results indicate that a linear-response approximation for the polarization of water solvent reaction near typical polar and charged protein groups is accurate to within approximately 90%.