Application of information theory to a three‐body coarse‐grained representation of proteins in the PDB: Insights into the structural and evolutionary roles of residues in protein structure

Knowledge‐based methods for analyzing protein structures, such as statistical potentials, primarily consider the distances between pairs of bodies (atoms or groups of atoms). Considerations of several bodies simultaneously are generally used to characterize bonded structural elements or those in close contact with each other, but historically do not consider atoms that are not in direct contact with each other. In this report, we introduce an information‐theoretic method for detecting and quantifying distance‐dependent through‐space multibody relationships between the sidechains of three residues. The technique introduced is capable of producing convergent and consistent results when applied to a sufficiently large database of randomly chosen, experimentally solved protein structures. The results of our study can be shown to reproduce established physico‐chemical properties of residues as well as more recently discovered properties and interactions. These results offer insight into the numerous roles that residues play in protein structure, as well as relationships between residue function, protein structure, and evolution. The techniques and insights presented in this work should be useful in the future development of novel knowledge‐based tools for the evaluation of protein structure. Proteins 2014; 82:3450–3465. © 2014 Wiley Periodicals, Inc.