title: Predicting nsSNPs that Disrupt Protein-Protein Interactions Using Docking.
abstract: The human genome contains a large number of protein polymorphisms due to individual genome variation. How many of these polymorphisms lead to altered protein-protein interaction is unknown. We have developed a method to address this question. The intersection of the SKEMPI database (of affinity constants among interacting proteins) and CAPRI 4.0 docking benchmark was docked using HADDOCK, leading to a training set of 166 mutant pairs. A random forest classifier based on the differences in resulting docking scores between the 166 mutant pairs and their wild-types was used, to distinguish between variants that have either completely or partially lost binding ability. Fifty percent of non-binders were correctly predicted with a false discovery rate of only 2 percent. The model was tested on a set of 15 HIV-1 - human, as well as seven human- human glioblastoma-related, mutant protein pairs: 50 percent of combined non-binders were correctly predicted with a false discovery rate of 10 percent. The model was also used to identify 10 protein-protein interactions between human proteins and their HIV-1 partners that are likely to be abolished by rare non-synonymous single-nucleotide polymorphisms (nsSNPs). These nsSNPs may represent novel and potentially therapeutically-valuable targets for anti-viral therapy by disruption of viral binding.
authors.forename: Norman
authors.initials: N
authors.lastname: Goodacre
authors.forename: Nathan
authors.initials: N
authors.lastname: Edwards
authors.forename: Mark
authors.initials: M
authors.lastname: Danielsen
authors.forename: Peter
authors.initials: P
authors.lastname: Uetz
authors.forename: Cathy
authors.initials: C
authors.lastname: Wu
mesh_terms: D019295:Computational Biology / Q000379:methods*; D006801:Humans; D000069550:Machine Learning; D015233:Models, Statistical; D062105:Molecular Docking Simulation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics*; D060066:Protein Interaction Maps / Q000235:genetics*