ArticleBMC genomics2012
On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutions.
Article in BMC genomics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed.
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- Mutations observed in somatic evolution reveal underlying gene mechanisms.Communications biology · 2023Article
- Turning Failures into Applications: The Problem of Protein ΔΔG Prediction.Methods in molecular biology (Clifton, N.J.) · 2022Article
- The structure-based cancer-related single amino acid variation prediction.Scientific reports · 2021Article
- Network analysis of dynamically important residues in protein structures mediating ligand-binding conformational changes.European biophysics journal : EBJ · 2019Article
- Homology modeling in a dynamical world.Protein science : a publication of the Protein Society · 2017Article
- Promiscuity in the Enzymatic Catalysis of Phosphate and Sulfate Transfer.Biochemistry · 2016Review
- Article
- CoDNaS 2.0: a comprehensive database of protein conformational diversity in the native state.Database : the journal of biological databases and curation · 2016Article
- Cynomolgus and pigtail macaque IgG subclasses: characterization of IGHG genes and computational analysis of IgG/Fc receptor binding affinity.Immunogenetics · 2014Article
- Structural dynamics flexibility informs function and evolution at a proteome scale.Evolutionary applications · 2013Article
- SNP-SIG Meeting 2011: identification and annotation of SNPs in the context of structure, function, and disease.BMC genomics · 2012Article
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Abstract
backgroundNon-synonymous coding SNPs (nsSNPs) that are associated to disease can also be related with alterations in protein stability. Computational methods are available to predict the effect of single amino acid substitutions (SASs) on protein stability based on a single folded structure. However, the native state of a protein is not unique and it is better represented by the ensemble of its conformers in dynamic equilibrium. The maintenance of the ensemble is essential for protein function. In this work we investigated how protein conformational diversity can affect the discrimination of neutral and disease related SASs based on protein stability estimations. For this purpose, we used 119 proteins with 803 associated SASs, 60% of which are disease related. Each protein was associated with its corresponding set of available conformers as found in the Protein Conformational Database (PCDB). Our dataset contains proteins with different extensions of conformational diversity summing up a total number of 1023 conformers.
resultsThe existence of different conformers for a given protein introduces great variability in the estimation of the protein stability (ΔΔG) after a single amino acid substitution (SAS) as computed with FoldX. Indeed, in 35% of our protein set at least one SAS can be described as stabilizing, destabilizing or neutral when a cutoff value of ±2 kcal/mol is adopted for discriminating neutral from perturbing SASs. However, when the ΔΔG variability among conformers is taken into account, the correlation among the perturbation of protein stability and the corresponding disease or neutral phenotype increases as compared with the same analysis on single protein structures. At the conformer level, we also found that the different conformers correlate in a different way to the corresponding phenotype.
conclusionsOur results suggest that the consideration of conformational diversity can improve the discrimination of neutral and disease related protein SASs based on the evaluation of the corresponding Gibbs free energy change.
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