Correlation between knowledge-based and detailed atomic potentials: application to the unfolding of the GCN4 leucine zipper

ABSTRACT The relationship between the un-folding pseudo free energies of reduced and de-tailed atomic models of the GCN4 leucine zipper is examined. Starting from the native crystal struc-ture, a large number of conformations ranging from folded to unfolded were generated by all-atom mo-lecular dynamics unfolding simulations in an aque-ous environment at elevated temperatures. For the detailed atomic model, the pseudo free energies are obtained by combining the CHARMM all-atom poten-tial with a solvation component from the general-ized Born, surface accessibility, GB/SA, model. Re-duced model energies were evaluated using a knowledge-based potential. Both energies are highly correlated. In addition, both show a good correla-tion with the root mean square deviation, RMSD, of the backbone from native. These results suggest that knowledge-based potentials are capable of de-scribing at least some of the properties of the folded as well as the unfolded states of proteins, even though they are derived from a database of native protein structures. Since only conformations gener-ated from an unfolding simulation are used, we cannot assess whether these potentials can discrimi-nate the native conformation from the manifold of alternative, low-energy misfolded states. Neverthe-less, these results also have significant implica-tions for the development of a methodology for multiscale modeling of proteins that combines reduced and detailed atomic models. Protein