Effect of Direct and Water-Mediated Interactions on the Identification of Hotspots in Biomolecular Complexes with Multiple Subsystems

Identification of important residues in biochemical complexes is often a crucial step for many problems in molecular biology and biochemistry. A method is proposed to identify hotspots in biomolecular complexes based on a new metric, derived from networks representing molecular subunits (residues, bridging solvent molecules, ligands etc.) connected by interactions. A singular value decomposition of the weighted adjacency matrix is used to construct a scalar rank for each subunit that reflects its importance in the residue interaction network. This metric is called the singular value centrality. In addition, a new formalism is proposed to account for water-mediated interactions in the ranking of residues. Interactions for a residue network can be provided by various computational methods. In this work interactions are obtained from full quantum-mechanical calculations of protein–protein complexes using the fragment molecular orbital method. The ranking results are shown to be in good agreement with earlier computational and experimental studies. The developed method can be used to gain a deeper insight into the role of subunits in complex biomolecular systems.