An aggregate analysis of many predicted structures to reduce errors in protein structure comparison caused by conformational flexibility

• Published in: BMC structural biology Vol. 13 Suppl 1; no. S1; p. S10
• Main Authors: Godshall, Brian G, Tang, Yisheng, Yang, Wenjie, Chen, Brian Y
• Format: Journal Article
• Language: English
• Published: England BioMed Central 2013
• Subjects: Algorithms; Binding Sites; Bioinformatics; Biophysics; Kinases; Ligands; Models, Molecular; Phosphopyruvate Hydratase - chemistry; Phosphopyruvate Hydratase - metabolism; Protein Binding; Protein Conformation; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - metabolism; Proteins; Structural Homology, Protein
• ISSN: 1472-6807; 1472-6807
• DOI: 10.1186/1472-6807-13-S1-S10

Conformational flexibility creates errors in the comparison of protein structures. Even small changes in backbone or sidechain conformation can radically alter the shape of ligand binding cavities. These changes can cause structure comparison programs to overlook functionally related proteins with remote evolutionary similarities, and cause others to incorrectly conclude that closely related proteins have different binding preferences, when their specificities are actually similar. Towards the latter effort, this paper applies protein structure prediction algorithms to enhance the classification of homologous proteins according to their binding preferences, despite radical conformational differences. Specifically, structure prediction algorithms can be used to "remodel" existing structures against the same template. This process can return proteins in very different conformations to similar, objectively comparable states. Operating on close homologs exploits the accuracy of structure predictions on closely related proteins, but structure prediction is often a nondeterministic process. Identical inputs can generate subtly different models with very different binding cavities that make structure comparison difficult. We present a first method to mitigate such errors, called "medial remodeling", that examines a large number of predicted structures to eliminate extreme models of the same binding cavity. Our results, on the enolase and tyrosine kinase superfamilies, demonstrate that remodeling can enable proteins in very different conformations to be returned to states that can be objectively compared. Structures that would have been erroneously classified as having different binding preferences were often correctly classified after remodeling, while structures that would have been correctly classified as having different binding preferences almost always remained distinct. The enolase superfamily, which exhibited less sequential diversity than the tyrosine kinase superfamily, was classified more accurately after remodeling than the tyrosine kinases. Medial remodeling reduced errors from models with unusual perturbations that distort the shape of the binding site, enhancing classification accuracy. This paper demonstrates that protein structure prediction can compensate for conformational variety in the comparison of protein-ligand binding sites. While protein structure prediction introduces new uncertainties into the structure comparison problem, our results indicate that unusual models can be ignored through an analysis of many models, using techniques like medial remodeling. These results point to applications of protein structure comparison that extend beyond existing crystal structures.