Investigating the linkage between disease-causing amino acid variants and their effect on protein stability and binding

By Yunhui Peng, Emil Alexov. 2016

52 citations recorded by the source corpus.

Single amino acid variations (SAV) occurring in human population result in natural differences between individuals or cause diseases. It is well understood that the molecular effect of SAV can be manifested as changes of the wild type characteristics of the corresponding protein, among which are the protein stability and protein interactions. Typically the effect of SAV on protein stability and interactions was assessed via the changes of the wild type folding and binding free energies. However, in terms of SAV affecting protein functionally and disease susceptibility, one wants to know to what extend the wild type function is perturbed by the SAV. Here it is demonstrated that relative, rather than the absolute, change of the folding and binding free energy serves as a good indicator for SAV association with disease. Using HumVar as a source for disease‐causing SAV and experimentally determined free energy changes from ProTherm and SKEMPI databases, correlation coefficients (CC) between the disease index (Pd) and relative folding (Ppr,f) and binding (Ppr,b) probability indexes, respectively, was achieved. The obtained CCs demonstrated the applicability of the proposed approach and it served as good indicator for SAV association with disease. Proteins 2016; 84:232–239. © 2015 Wiley Periodicals, Inc.

Subfields: General Arts and Humanities, Sociology and Political Science

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Citations in the corpus

SKEMPI 2.0: an updated benchmark of changes in protein–protein binding energy, kinetics and thermodynamics upon mutation (2018, methodology): “SKEMPI has also been used to study human disease (Petukh et al., 2015a; Das et al., 2014; Peng and Alexov, 2016), assessing”
Variation Interpretation Predictors: Principles, Types, Performance, and Choice (2016, background): “Incorrectfoldinganddecreasedstabilityarethemajorconsequences of pathogenic amino acid substitutions [Wang and Moult, 2001; Ferrer-Costa et al., 2002; Steﬂ et al., 2013; Peng and Alexov, 2016].”