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

Publication Type:

Journal Article

Source:

BMC struct biol, BioMed Central Ltd, Volume 13, Number Suppl 1, p.S10 (2013)

Abstract:

Background: 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. Methods: 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. Results: 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.

© IMRC CAS 2016