Structural and computational characterization of disease-related mutations involved in protein-protein interfaces
Navío, D. (Barcelona Supercomputing Center)
Rosell, M. (Barcelona Supercomputing Center)
Aguirre, Josu (Hospital Universitari Vall d'Hebron)
de la Cruz, Xavier (Institució Catalana de Recerca i Estudis Avançats)
Fernández-Recio, Juan (Universidad de La Rioja. Instituto de Ciencias de la Vid y del Vino)

Date:	2019
Abstract:	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.
Grants:	Agencia Estatal de Investigación BIO2016-79930-R Agencia Estatal de Investigación SAF2016-80255-R
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Protein-protein interactions ; Single amino acid variants ; Structural bioinformatics; ; Computational docking ; Interface prediction
Published in:	International journal of molecular sciences, Vol. 20 Núm. 7 (january 2019) , p. 1583, ISSN 1422-0067

DOI: 10.3390/ijms20071583
PMID: 30934865

15 p, 1.7 MB

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