Effect of Direct\nand Water-Mediated Interactions on\nthe Identification of Hotspots in Biomolecular Complexes with Multiple\nSubsystems

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