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Functional and Structural Features of Disease-Related Protein Variants
Open AccessArticle

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

1
Barcelona Supercomputing Center (BSC), 08034 Barcelona, Spain
2
Vall d’Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
3
Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
4
Institut de Biologia Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), 08028 Barcelona, Spain
5
Instituto de Ciencias de la Vid y del Vino (ICVV), CSIC—Universidad de La Rioja—Gobierno de La Rioja, 26007 Logroño, Spain
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(7), 1583; https://doi.org/10.3390/ijms20071583
Received: 1 March 2019 / Revised: 26 March 2019 / Accepted: 27 March 2019 / Published: 29 March 2019
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. View Full-Text
Keywords: protein-protein interactions; single amino acid variants; structural bioinformatics; computational docking; interface prediction protein-protein interactions; single amino acid variants; structural bioinformatics; computational docking; interface prediction
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MDPI and ACS Style

Navío, D.; Rosell, M.; Aguirre, J.; de la Cruz, X.; Fernández-Recio, J. Structural and Computational Characterization of Disease-Related Mutations Involved in Protein-Protein Interfaces. Int. J. Mol. Sci. 2019, 20, 1583. https://doi.org/10.3390/ijms20071583

AMA Style

Navío D, Rosell M, Aguirre J, de la Cruz X, Fernández-Recio J. Structural and Computational Characterization of Disease-Related Mutations Involved in Protein-Protein Interfaces. International Journal of Molecular Sciences. 2019; 20(7):1583. https://doi.org/10.3390/ijms20071583

Chicago/Turabian Style

Navío, Dàmaris; Rosell, Mireia; Aguirre, Josu; de la Cruz, Xavier; Fernández-Recio, Juan. 2019. "Structural and Computational Characterization of Disease-Related Mutations Involved in Protein-Protein Interfaces" Int. J. Mol. Sci. 20, no. 7: 1583. https://doi.org/10.3390/ijms20071583

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