title: Predicting the Impact of Missense Mutations on Protein-Protein Binding Affinity.
abstract: The crucial prerequisite for proper biological function is the protein's ability to establish highly selective interactions with macromolecular partners. A missense mutation that alters the protein binding affinity may cause significant perturbations or complete abolishment of the function, potentially leading to diseases. The availability of computational methods to evaluate the impact of mutations on protein-protein binding is critical for a wide range of biomedical applications. Here, we report an efficient computational approach for predicting the effect of single and multiple missense mutations on protein-protein binding affinity. It is based on a well-tested simulation protocol for structure minimization, modified MM-PBSA and statistical scoring energy functions with parameters optimized on experimental sets of several thousands of mutations. Our simulation protocol yields very good agreement between predicted and experimental values with Pearson correlation coefficients of 0.69 and 0.63 and root-mean-square errors of 1.20 and 1.90 kcal mol-1for single and multiple mutations, respectively. Compared with other available methods, our approach achieves high speed and prediction accuracy and can be applied to large datasets generated by modern genomics initiatives. In addition, we report a crucial role of water model and the polar solvation energy in estimating the changes in binding affinity. Our analysis also reveals that prediction accuracy and effect of mutations on binding strongly depends on the type of mutation and its location in a protein complex.
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health , Bethesda, Maryland 20894, United States.
authors.forename: Minghui
authors.initials: M
authors.lastname: Li
authors.affiliation: Computational Biophysics and Bioinformatics, Department of Physics, Clemson University , Clemson, South Carolina 29634, United States.
authors.forename: Marharyta
authors.initials: M
authors.lastname: Petukh
authors.affiliation: Computational Biophysics and Bioinformatics, Department of Physics, Clemson University , Clemson, South Carolina 29634, United States.
authors.forename: Emil
authors.initials: E
authors.lastname: Alexov
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health , Bethesda, Maryland 20894, United States.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Panchenko