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

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 (<i>p</i> < 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.

Bibliographic Details

Main Authors:	Navío, Dàmaris, Rosell, Mireia, Aguirre, Josu, Cruz, Xavier de la, Fernández-Recio, Juan
Other Authors:	Consejo Superior de Investigaciones Científicas (España)
Format:	artículo biblioteca
Published:	Multidisciplinary Digital Publishing Institute 2019-03-29
Subjects:	Protein-protein interactions, Single amino acid variants, Structural bioinformatics, Computational docking, Interface prediction,
Online Access:	http://hdl.handle.net/10261/180175 http://dx.doi.org/10.13039/501100000780 http://dx.doi.org/10.13039/100013276 http://dx.doi.org/10.13039/501100003329 http://dx.doi.org/10.13039/501100003339
Tags:	Add Tag No Tags, Be the first to tag this record!