Protein Structure Refinement Guided by Atomic Packing Frustration Analysis.

Abstract

Recent advances in machine learning, bioinformatics, and the understanding of the folding problem have enabled efficient predictions of protein structures with moderate accuracy, even for targets where there is little information from templates. All-atom molecular dynamics simulations provide a route to refine such predicted structures, but unguided atomistic simulations, even when lengthy in time, often fail to eliminate incorrect structural features that would prevent the structure from becoming more energetically favorable owing to the necessity of making large scale motions and to overcoming energy barriers for side chain repacking. In this study, we show that localizing packing frustration at atomic resolution by examining the statistics of the energetic changes that occur when the local environment of a site is changed allows one to identify the most likely locations of incorrect contacts. The global statistics of atomic resolution frustration in structures that have been predicted using various algorithms provide strong indicators of structural quality when tested over a database of 20 targets from previous CASP experiments. Residues that are more correctly located turn out to be more minimally frustrated than more poorly positioned sites. These observations provide a diagnosis of both global and local quality of predicted structures and thus can be used as guidance in all-atom refinement simulations of the 20 targets. Refinement simulations guided by atomic packing frustration turn out to be quite efficient and significantly improve the quality of the structures.