A critical analysis of continuum electrostatics: the screened Coulomb potential--implicit solvent model and the study of the alanine dipeptide and discrimination of misfolded structures of proteins

An analysis of the screened Coulomb potential--implicit solvent model (SCP--ISM) is presented showing that general equations for both the electrostatic and solvation free energy can be derived in a continuum approach, using statistical averaging of the polarization field created by the solvent around the molecule. The derivation clearly shows how the concept of boundary, usually found in macroscopic approaches, is eliminated when the continuum model is obtained from a microscopic treatment using appropriate averaging techniques. The model is used to study the alanine dipeptide in aqueous solution, as well as the discrimination of native protein structures from misfolded conformations. For the alanine dipeptide the free energy surface in the phi--psi space is calculated and compared with recently reported results of a detailed molecular dynamics simulation using an explicit representation of the solvent, and with other available data. The study showed that the results obtained using the SCP--ISM are comparable to those of the explicit water calculation and compares favorably to the FDPB approach. Both transition states and energy minima show a high correlation (r > 0.98) with the results obtained in the explicit water analysis. The study of the misfolded structures of proteins comprised the analysis of three standard decoy sets, namely, the EMBL, Park and Levitt, and Baker's CASP3 sets. In all cases the SCP--ISM discriminated well the native structures of the proteins, and the best-predicted structures were always near-native (cRMSD approximately 2 A).