Centrality Measures in Residue Interaction Networks to Highlight Amino Acids in Protein–Protein Binding

Residue Interaction Networks (RINs) describe a protein structure as a network of interacting residues. Central nodes in these networks, identified by centrality analyses, highlight those residues that play a role in the structure and function of the protein. However, little is known about the capability of such analyses to identify residues involved in the formation of macromolecular complexes. Here we performed six different centrality measures on the RINs generated from the complexes of the SKEMPI 2 database of changes in protein-protein binding upon mutation, in order to evaluate the capability of each of these measures to identify major binding residues. The analyses were performed with and without the crystallographic water molecules, in addition to the protein residues. We also investigated the use of a weight factor based on the inter-residue distances to improve the detection of these residues. We show that for the identification of major binding residues, closeness, degree and PageRank result in good precision, whereas betweenness, eigenvector and residue centrality analyses rather give a higher sensitivity. Including water in the analysis improves the sensitivity of all measures without losing precision. Applying weights only slightly raises the sensitivity of eigenvector centrality analysis. We finally show that a combination of multiple centrality analyses is the optimal approach to identify residues that play a role in protein-protein interaction.