Structural Modeling and In Silico Analysis of Human Superoxide Dismutase 2

Aging in the world population has increased every year. Superoxide dismutase2 (Mn-SOD or SOD2) protects against oxidative stress, a main factor influencingcellular longevity. Polymorphisms in SOD2 have been associated with the developmentof neurodegenerative diseases, such as Alzheimer’s and Parkinson’sdisease, as well as psychiatric disorders, such as schizophrenia, depressionand bipolar disorder. In this study, all of the described natural variants(S10I, A16V, E66V, G76R, I82T and R156W) of SOD2 were subjected to insilico analysis using eight different algorithms: SNPeffect, PolyPhen-2,PhD-SNP, PMUT, SIFT, SNAP, SNPs&GO and nsSNPAnalyzer. This analysis revealeddisparate results for a few of the algorithms. The results showed that, fromat least one algorithm, each amino acid substitution appears to harmfullyaffect the protein. Structural theoretical models were created for variantsthrough comparative modelling performed using the MHOLline server (which includesMODELLER and PROCHECK) and ab initio modelling, using theI-Tasser server. The predicted models were evaluated using TM-align, and theresults show that the models were constructed with high accuracy. The RMSDvalues of the modelled mutants indicated likely pathogenicity for all missensemutations. Structural phylogenetic analysis using ConSurf revealed that humanSOD2 is highly conserved. As a result, a human-curated database was generatedthat enables biologists and clinicians to explore SOD2 nsSNPs, including predictionsof their effects and visualisation of the alignment of both the wild-typeand mutant structures. The database is freely available at http://bioinfogroup.com/databaseand will be regularly updated.