Structural and Computational Characterization of Disease-Related Mutations Involved in Protein-Protein Interfaces

Abstract

Computational docking; Interface prediction; Protein-protein interactions

Acoblament molecular computacional; Predicció d'interfícies; Interaccions proteïna-proteïna

Acoplamiento molecular computacional; Predicción de interfaces; Interacciones proteína-proteína

One of the known potential effects of disease-causing amino acid substitutions in proteins is to modulate protein-protein interactions (PPIs). To interpret such variants at the molecular level and to obtain useful information for prediction purposes, it is important to determine whether they are located at protein-protein interfaces, which are composed of two main regions, core and rim, with different evolutionary conservation and physicochemical properties. Here we have performed a structural, energetics and computational analysis of interactions between proteins hosting mutations related to diseases detected in newborn screening. Interface residues were classified as core or rim, showing that the core residues contribute the most to the binding free energy of the PPI. Disease-causing variants are more likely to occur at the interface core region rather than at the interface rim (p < 0.0001). In contrast, neutral variants are more often found at the interface rim or at the non-interacting surface rather than at the interface core region. We also found that arginine, tryptophan, and tyrosine are over-represented among mutated residues leading to disease. These results can enhance our understanding of disease at molecular level and thus contribute towards personalized medicine by helping clinicians to provide adequate diagnosis and treatments.

This research was funding by the EU European Regional Development Fund (ERDF) through the Program Interreg V-A Spain-France-Andorra (POCTEFA), by the CSIC (intramural grant number 201720I031), and by the Spanish Ministry of Economy and Competitiveness (grants BIO2016-79930-R and SAF2016-80255-R). M.R. is recipient of an FPI fellowship from the Severo Ochoa program.