Discrimination of the native from misfolded protein models with an energy function including implicit solvation

An essential requirement for theoretical protein structure prediction is an energy function that can discriminate the native from non-native protein c onformations. To date most of the energy functions used for this purpose ha ve been extracted from a statistical analysis of the protein structure data base, without explicit reference to the physical interactions responsible f or protein stability. The use of the statistical functions has been support ed by the widespread belief that they are superior for such discrimination to physics-based energy functions. An effective energy function which combi ned the CHARMM vacuum potential with a Gaussian model for the solvation fre e energy is tested for its ability to discriminate the native structure of a protein from misfolded conformations; the results are compared with those obtained with the vacuum CHARMM potential. The test is performed on severa l sets of misfolded structures prepared by others, including sets of about 650 good decoys for six proteins, as well as on misfolded structures of chy motrypsin inhibitor 2. The vacuum CHARMM potential is successful in most ca ses when energy minimized conformations are considered, but fails when appl ied to structures relaxed by molecular dynamics. With the effective energy function the native state is always more stable than grossly misfolded conf ormations both in energy minimized and molecular dynamics-relaxed structure s. The present results suggest that molecular mechanics (physics-based) ene rgy functions, complemented by a simple model for the solvation free energy , should be tested for use in the inverse folding problem, and supports the ir use in studies of the effective energy surface of proteins in solution. Moreover, the study suggests that the belief in the superiority of statisti cal functions for these purposes may be ill founded. (C) 1999 Academic Pres s.