Protein homology model refinement by large-scale energy optimization

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 12; pp. 3054 - 3059
• Main Authors: Park, Hahnbeom, Ovchinnikov, Sergey, Kim, David E., DiMaio, Frank, Baker, David
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20-03-2018
• Subjects: Accuracy; Biological Sciences; Computational Biology - methods; Computer Simulation; Free energy; Homology; Model accuracy; Models, Chemical; Models, Molecular; Molecular Dynamics Simulation; Optimization; Protein Conformation; Protein families; Protein Folding; Protein structure; Proteins; Searching; Success; Thermodynamics; energy function; homology modeling; protein structure refinement; protein structure prediction; protein conformational search
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1719115115

Proteins fold to their lowest free-energy structures, and hence the most straightforward way to increase the accuracy of a partially incorrect protein structure model is to search for the lowest-energy nearby structure. This direct approach has met with little success for two reasons: first, energy function inaccuracies can lead to false energy minima, resulting in model degradation rather than improvement; and second, even with an accurate energy function, the search problem is formidable because the energy only drops considerably in the immediate vicinity of the global minimum, and there are a very large number of degrees of freedom. Here we describe a large-scale energy optimization-based refinement method that incorporates advances in both search and energy function accuracy that can substantially improve the accuracy of low-resolution homology models. The method refined low-resolution homology models into correct folds for 50 of 84 diverse protein families and generated improved models in recent blind structure prediction experiments. Analyses of the basis for these improvements reveal contributions from both the improvements in conformational sampling techniques and the energy function.