Improved protein structure selection using decoy-dependent discriminatory functions

BACKGROUND: A key component in protein structure prediction is a scoring or discriminatory function that can distinguish near-native conformations from misfolded ones. Various types of scoring functions have been developed to accomplish this goal, but their performance is not adequate to solve the structure selection problem. In addition, there is poor correlation between the scores and the accuracy of the generated conformations. RESULTS: We present a simple and nonparametric formula to estimate the accuracy of predicted conformations (or decoys). This scoring function, called the density score function, evaluates decoy conformations by performing an all-against-all C(α )RMSD (Root Mean Square Deviation) calculation in a given decoy set. We tested the density score function on 83 decoy sets grouped by their generation methods (4state_reduced, fisa, fisa_casp3, lmds, lattice_ssfit, semfold and Rosetta). The density scores have correlations as high as 0.9 with the C(α )RMSDs of the decoy conformations, measured relative to the experimental conformation for each decoy. We previously developed a residue-specific all-atom probability discriminatory function (RAPDF), which compiles statistics from a database of experimentally determined conformations, to aid in structure selection. Here, we present a decoy-dependent discriminatory function called self-RAPDF, where we compiled the atom-atom contact probabilities from all the conformations in a decoy set instead of using an ensemble of native conformations, with a weighting scheme based on the density scores. The self-RAPDF has a higher correlation with C(α )RMSD than RAPDF for 76/83 decoy sets, and selects better near-native conformations for 62/83 decoy sets. Self-RAPDF may be useful not only for selecting near-native conformations from decoy sets, but also for fold simulations and protein structure refinement. CONCLUSIONS: Both the density score and the self-RAPDF functions are decoy-dependent scoring functions for improved protein structure selection. Their success indicates that information from the ensemble of decoy conformations can be used to derive statistical probabilities and facilitate the identification of near-native structures.