Can a physics-based, all-atom potential find a protein's native structure among misfolded structures? I. Large scale AMBER benchmarking

Recent work has shown that physics-based, all-atom energy functions (AMBER, CHARMM, OPLS-AA) and local minimization, when used in scoring, are able to discriminate among native and decoy structures. Yet, there have been only few instances reported of the successful use of physics based potentials in the actual refinement of protein models from a starting conformation to one that ends in structures, which are closer to the native state. An energy function that has a global minimum energy in the protein's native state and a good correlation between energy and nativelikeness should be able to drive model structures closer to their native structure during a conformational search. Here, the possible reasons for the discrepancy between the scoring and refinement results for the case of AMBER potential are examined. When the conformational search via molecular dynamics is driven by the AMBER potential for a large set of 150 nonhomologous proteins and their associated decoys, often the native minimum does not appear to be the lowest free energy state. Ways of correcting the potential function in order to make it more suitable for protein model refinement are proposed. (c) 2007 Wiley Periodicals, Inc.