Abstract
Aging in the world population has increased every year. Superoxide dismutase 2 (Mn-SOD or SOD2) protects against oxidative stress, a main factor influencing cellular longevity. Polymorphisms in SOD2 have been associated with the development of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, as well as psychiatric disorders, such as schizophrenia, depression and bipolar disorder. In this study, all of the described natural variants (S10I, A16V, E66V, G76R, I82T and R156W) of SOD2 were subjected to in silico analysis using eight different algorithms: SNPeffect, PolyPhen-2, PhD-SNP, PMUT, SIFT, SNAP, SNPs&GO and nsSNPAnalyzer. This analysis revealed disparate results for a few of the algorithms. The results showed that, from at least one algorithm, each amino acid substitution appears to harmfully affect the protein. Structural theoretical models were created for variants through comparative modelling performed using the MHOLline server (which includes MODELLER and PROCHECK) and ab initio modelling, using the I-Tasser server. The predicted models were evaluated using TM-align, and the results show that the models were constructed with high accuracy. The RMSD values of the modelled mutants indicated likely pathogenicity for all missense mutations. Structural phylogenetic analysis using ConSurf revealed that human SOD2 is highly conserved. As a result, a human-curated database was generated that enables biologists and clinicians to explore SOD2 nsSNPs, including predictions of their effects and visualisation of the alignment of both the wild-type and mutant structures. The database is freely available at http://bioinfogroup.com/database and will be regularly updated.
Highlights
Aging is a multifactorial process, there is significant evidence that shows that oxidative stress is one of the main factors that influences cellular longevity
The disproportionate rate of intrauterine death and early fatality in Mn-Superoxide dismutases (SODs) knock-out animals demonstrated the importance of Mn-SOD, rather than SOD1 and SOD3, in foetal development. [1]
Polymorphisms in SOD2 have been associated with the development of neurodegenerative diseases, such as Alzheimer’s [2] (A16V) and Parkinson’s disease [3] [4] [1] (A16V and I82T), as well as psychiatric disorders, such as schizophrenia [5], depression [6] and bipolar disorder [7]
Summary
Aging is a multifactorial process, there is significant evidence that shows that oxidative stress is one of the main factors that influences cellular longevity. We collected the natural variants of SOD2 for in silico analysis, which can determine whether these variants influence the protein’s three-dimensional structure or stability. Possible effects of the missense variants on protein function could be inferred using bioinformatics tools designed for these types of interpretation, such as PolyPhen-2 [15]. Non-synonymous SNP Analysis The functional effects of non-synonymous single-nucleotide substitutions (nsSNPs) were predicted using the following programmes: PhD-SNP [17], PMUT [18], PolyPhen-2 [15], SIFT (Sorting Intolerant from Tolerant) [19], SNAP [20,21], SNPs&GO [22] and nsSNPAnalyzer [23].
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