Computer modeling of protein folding: conformational and energetic analysis of reduced and detailed protein models

Recently we developed methods to generate low-resolution protein tertiary structures using a reduced model of the protein where secondary structure is specified and a simple potential based on a statistical analysis of the Protein Data Bank is employed. Here we present the results of an extensive analysis of a large number of detailed, all-atom structures generated from these reduced model structures. Following side-chain addition, minimization and simulated annealing simulations are carried out with a molecular mechanics potential including an approximate continuum solvent treatment. By combining reduced model simulations with molecular modeling calculations we generate energetically competitive, plausible misfolded structures which provide a more significant test of the potential function than current misfolded models based on superimposing the native sequence on the folded structures of completely different proteins. The various contributions to the total energy and their interdependence are analyzed in detail for many conformations of three proteins (myoglobin, the C-terminal fragment of the L7/L12 ribosomal protein, and the N-terminal domain of phage 434 repressor). Our analysis indicates that the all-atom potential performs reasonably well in distinguishing the native structure. It also reveals inadequacies in the reduced model potential, which suggests how this potential can be improved to yield greater accuracy. Preliminary results with an improved potential are presented.