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.
Highlights
Non-synonymous coding SNPs that are associated to disease can be related with alterations in protein stability
Our results suggest that the consideration of conformational diversity can improve the discrimination of neutral and disease related protein single amino acid substitutions (SASs) based on the evaluation of the corresponding Gibbs free energy change
Considering that the average root mean squared deviation (RMSD) for a protein crystallized under the same condition ranges from 0.1 and 0.4 Å [42] and from the distribution shown in Figure 1, we concluded that our dataset contains proteins with moderated to extreme conformational diversity
Summary
Non-synonymous coding SNPs (nsSNPs) that are associated to disease can be related with alterations in protein stability. In this work we investigated how protein conformational diversity can affect the discrimination of neutral and disease related SASs based on protein stability estimations. The less frequently found [1], the most obvious mechanism at the disease origin is due to change of key residues participating directly in protein function. This is the case when residue substitution occurs at the active site or in binding-sites for substrate and/or allosteric regulators [2,3,4]. The correlation among protein SASs and their involvement in human diseases has been proven to be moderate [11], suggesting that change in protein stability is not the only source of diseases
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