Local solvent dielectrics and destabilization of solvent-exposed states in folding proteins

Implicit-solvent treatments of protein folding dynamics require that we account for conformation-dependent environments surrounding intramolecular interactions. This goal may be achieved by introducing correlations that model third-body participation in the effective destabilization of solvent-exposed states. A continuous treatment of the local solvent dielectric is implemented to deal with such correlations and is based on the assessment of alterations of solvent structure due to the presence of the third body. The analytical results are incorporated in an ab initio folding algorithm with no bias towards known target structures. In cases where the algorithm folds the protein with reasonable accuracy (RMSD∼5Å), our results indicate that three-body correlations are responsible for cooperative effects signaled by a sudden and sizable increase in contact order and decrease in internal energy. These synergistics beget the overall two-state kinetics observed in the folding of moderate size proteins.