title: PCRPi: Presaging Critical Residues in Protein interfaces, a new computational tool to chart hot spots in protein interfaces.
abstract: Protein-protein interactions (PPIs) are ubiquitous in Biology, and thus offer an enormous potential for the discovery of novel therapeutics. Although protein interfaces are large and lack defining physiochemical traits, is well established that only a small portion of interface residues, the so-called hot spot residues, contribute the most to the binding energy of the protein complex. Moreover, recent successes in development of novel drugs aimed at disrupting PPIs rely on targeting such residues. Experimental methods for describing critical residues are lengthy and costly; therefore, there is a need for computational tools that can complement experimental efforts. Here, we describe a new computational approach to predict hot spot residues in protein interfaces. The method, called Presaging Critical Residues in Protein interfaces (PCRPi), depends on the integration of diverse metrics into a unique probabilistic measure by using Bayesian Networks. We have benchmarked our method using a large set of experimentally verified hot spot residues and on a blind prediction on the protein complex formed by HRAS protein and a single domain antibody. Under both scenarios, PCRPi delivered consistent and accurate predictions. Finally, PCRPi is able to handle cases where some of the input data is either missing or not reliable (e.g. evolutionary information).
authors.affiliation: Leeds Institute of Molecular Medicine, Section of Experimental Therapeutics, St James's University Hospital, University of Leeds, Leeds, LS9 7TF, UK.
authors.forename: Salam A
authors.initials: SA
authors.lastname: Assi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Terence H
authors.initials: TH
authors.lastname: Rabbitts
authors.forename: Narcis
authors.initials: N
authors.lastname: Fernandez-Fuentes
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D001499:Bayes Theorem; D019295:Computational Biology; D007135:Immunoglobulin Variable Region / Q000737:chemistry; D008958:Models, Molecular; D011487:Protein Conformation; D025941:Protein Interaction Mapping / Q000379:methods*; D011506:Proteins / Q000737:chemistry; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry / Q000276:immunology; D012984:Software
chemical_list: D000596:Amino Acids; D007135:Immunoglobulin Variable Region; D011506:Proteins; D016283:Proto-Oncogene Proteins p21(ras)