Mining protein dynamics from sets of crystal structures using “consensus structures”

Abstract

In this work, we describe two novel approaches to utilize the dynamic structure information implicitly contained in large crystal structure data sets. The first approach visualizes both consistent as well as variable ligand-induced changes in ligand-bound compared with apo protein crystal structures. For this purpose, information was mined from B-factors and ligand-induced residue displacements in multiple crystal structures, minimizing experimental error and noise. With this approach, the mechanism of action of non-nucleoside reverse transcriptase inhibitors (NNRTIs) as an inseparable combination of distortion of protein dynamics and conformational changes of HIV-1 reverse transcriptase was corroborated (a combination of the previously proposed “molecular arthritis” and “distorted site” mechanisms). The second approach presented here uses “consensus structures” to map common binding features that are present in a set of structures of NNRTI-bound HIV-1 reverse transcriptase. Consensus structures are based on different levels of structural overlap of multiple crystal structures and are used to analyze protein–ligand interactions. The structures are shown to yield information about conserved hydrogen bonding interactions as well as binding-pocket flexibility, shape, and volume. From the consensus structures, a common wild type NNRTI binding pocket emerges. Furthermore, we were able to identify a conserved backbone hydrogen bond acceptor at P236 and a novel hydrophobic subpocket, which are not yet utilized by current drugs. Our methods introduced here reinterpret the atom information and make use of the data variability by using multiple structures, complementing classical 3D structural information of single structures.