Protein structure refinement by optimization

Knowledge-based protein potentials are simplified potentials designed to improve the quality of protein models, which is important as more accurate models are more useful for biological and pharmaceutical studies. Consequently, knowledge-based potentials often are designed to be efficient in ordering a given set of deformed structures denoted decoys according to how close they are to the relevant native protein structure. This, however, does not necessarily imply that energy minimization of this potential will bring the decoys closer to the native structure. In this study, we introduce an iterative strategy to improve the convergence of decoy structures. It works by adding energy optimized decoys to the pool of decoys used to construct the next and improved knowledge-based potential. We demonstrate that this strategy results in significantly improved decoy convergence on Titan high resolution decoys and refinement targets from Critical Assessment of protein Structure Prediction competitions. Our potential is formulated in Cartesian coordinates and has a fixed backbone potential to restricts motions to be close to those of a dihedral model, a fixed hydrogen-bonding potential and a variable coarse grained carbon alpha potential consisting of a pair potential and a novel solvent potential that are b-spline based as we use explicit gradient and Hessian for efficient energy optimization.