Ab initio construction of polypeptide fragments: Accuracy of loop decoy discrimination by an all‐atom statistical potential and the AMBER force field with the Generalized Born solvation model

The accuracy of model selection from decoy ensembles of protein loop conformations was explored by comparing the performance of the Samudrala-Moult all-atom statistical potential (RAPDF) and the AMBER molecular mechanics force field, including the Generalized Born/surface area solvation model. Large ensembles of consistent loop conformations, represented at atomic detail with idealized geometry, were generated for a large test set of protein loops of 2 to 12 residues long by a novel ab initio method called RAPPER that relies on fine-grained residue-specific phi/psi propensity tables for conformational sampling. Ranking the conformers on the basis of RAPDF scores resulted in selected conformers that had an average global, non-superimposed RMSD for all heavy mainchain atoms ranging from 1.2 A for 4-mers to 2.9 A for 8-mers to 6.2 A for 12-mers. After filtering on the basis of anchor geometry and RAPDF scores, ranking by energy minimization of the AMBER/GBSA potential energy function selected conformers that had global RMSD values of 0.5 A for 4-mers, 2.3 A for 8-mers, and 5.0 A for 12-mers. Minimized fragments had, on average, consistently lower RMSD values (by 0.1 A) than their initial conformations. The importance of the Generalized Born solvation energy term is reflected by the observation that the average RMSD accuracy for all loop lengths was worse when this term is omitted. There are, however, still many cases where the AMBER gas-phase minimization selected conformers of lower RMSD than the AMBER/GBSA minimization. The AMBER/GBSA energy function had better correlation with RMSD to native than the RAPDF. When the ensembles were supplemented with conformations extracted from experimental structures, a dramatic improvement in selection accuracy was observed at longer lengths (average RMSD of 1.3 A for 8-mers) when scoring with the AMBER/GBSA force field. This work provides the basis for a promising hybrid approach of ab initio and knowledge-based methods for loop modeling.