LoCo: a novel main chain scoring function for protein structure prediction based on local coordinates.

BACKGROUND: Successful protein structure prediction requires accurate low-resolution scoring functions so that protein main chain conformations that are close to the native can be identified. Once that is accomplished, a more detailed and time-consuming treatment to produce all-atom models can be undertaken. The earliest low-resolution scoring used simple distance-based "contact potentials," but more recently, the relative orientations of interacting amino acids have been taken into account to improve performance. RESULTS: We developed a new knowledge-based scoring function, LoCo, that locates the interaction partners of each individual residue within a local coordinate system based only on the position of its main chain N, Cα and C atoms. LoCo was trained on a large set of experimentally determined structures and optimized using standard sets of modeled structures, or "decoys." No structure used to train or optimize the function was included among those used to test it. When tested against 29 other published main chain functions on a group of 77 commonly used decoy sets, our function outperformed all others in Cα RMSD rank of the best-scoring decoy, with statistically significant p-values < 0.05 for 26 out of the 29 other functions considered. LoCo is fast, requiring on average less than 6 microseconds per residue for interaction and scoring on commonly-used computer hardware. CONCLUSIONS: Our function demonstrates an unmatched combination of accuracy, speed, and simplicity and shows excellent promise for protein structure prediction. Broader applications may include protein-protein interactions and protein design.

Protein-protein docking predictions for the CAPRI experiment.

We predicted structures for all seven targets in the CAPRI experiment using a new method in development at the time of the challenge. The technique includes a low-resolution rigid body Monte Carlo search followed by high-resolution refinement with side-chain conformational changes and rigid body minimization. Decoys (approximately 10(6) per target) were discriminated using a scoring function including van der Waals and solvation interactions, hydrogen bonding, residue-residue pair statistics, and rotamer probabilities. Decoys were ranked, clustered, manually inspected, and selected. The top ranked model for target 6 predicted the experimental structure to 1.5 A RMSD and included 48 of 65 correct residue-residue contacts. Target 7 was predicted at 5.3 A RMSD with 22 of 37 correct residue-residue contacts using a homology model from a known complex structure. Using a preliminary version of the protocol in round 1, target 1 was predicted within 8.8 A although few contacts were correct. For targets 2 and 3, the interface locations and a small fraction of the contacts were correctly identified.