USING A HYDROPHOBIC CONTACT POTENTIAL TO EVALUATE NATIVE AND NEAR-NATIVE FOLDS GENERATED BY MOLECULAR-DYNAMICS SIMULATIONS

There are several knowledge-based energy functions that can distinguis h the native fold from a pool of grossly misfolded decoys for a given sequence of amino acids. These decoys, which are typically generated b y mounting, or ''threading'', the sequence onto the backbones of unrel ated protein structures, tend to be non-compact and quite different fr om the native structure: the root-mean-squared (RMS) deviations fron t he native are commonly in the range of 15 to 20 Angstrom. Effective en ergy functions should also demonstrate a similar recognition capabilit y when presented with compact decoys that depart only slightly in conf ormation from the correct structure (i.e. those with RMS deviations of similar to 5 Angstrom or less). Recently, we developed a simple yet p owerful method for native fold recognition based on the tendency for n ative folds to form hydrophobic cores. Our energy measure, which we ca ll the hydrophobic fitness score, is challenged to recognize the nativ e fold from 2000 near-native structures generated for each of five sma ll monomeric proteins. First, 1000 conformations for each protein were generated by molecular dynamics simulation at room temperature. The a verage RMS deviation of this set of 5000 was 1.5 Angstrom. A total of 323 decoys had energies lower than native; however, none of these had RMS deviations greater than 2 Angstrom. Another 1000 structures were g enerated for each at high temperature, in which a greater range of con formational space was explored (4.3 Angstrom average RMS deviation). O ut of this set, only seven decoys were misrecognized. The hydrophobic fitness energy of a conformation is strongly dependent upon the RMS de viation. On average our potential yields energy values which are lowes t for the population of structures generated at room temperature, inte rmediate for those produced at high temperature and highest for those constructed by threading methods. In general, the lowest energy decoy conformations have backbones very close to native structure. The possi ble utility of our method for screening backbone candidates for the pu rpose of modelling by side-chain packing optimization is discussed. (C ) 1996 Academic Press Limited