Structural Modeling and In Silico Analysis of Human Superoxide Dismutase 2

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.

Uncovering Neurodegenerative Protein Modifications via Proteomic Profiling

“…We next used the I-Tasser server to perform ab initio protein modeling (De Carvalho & De Mesquita, 2013;Roy, Kucukural, & Zhang, 2010;Zhang, 2008) which enabled us to construct models of both Figure 4 Structural models of Na + /K + -ATPase catalytic site in (A) E1P (Nyblom et al, 2013) and (B) E2P (Shinoda et al, 2009) conformations (PDB ID 4HQJ and 2ZXE, respectively). In both (A) and (B), color changes gradually from amino terminal (blue (dark gray in the print version)) to carboxyl terminal (red (gray in the print version)): A domain is in blue (dark gray in the print version) and cyan (light gray in the print version), P domain is in yellow (light gray in the print version), and N domain is in green (light gray in the print version).…”

Amyotrophic Lateral Sclerosis Type 20 - In Silico Analysis and Molecular Dynamics Simulation of hnRNPA1

“…In this work, computational biology methods were applied, following the methodology previously described by our group [ 10 , 11 ], to an in silico analysis of hnRNPA1 protein, which has been described as the cause of familial Amyotrophic Lateral Sclerosis type 20, aiming for a thorough analysis of the protein structure and its natural variants, as well as the effects of structural changes in the disease development.…”

Prediction of the Damage-Associated Non-Synonymous Single Nucleotide Polymorphisms in the Human MC1R Gene

“…In order to combine the results of the various tools, consensus predictors have been developed to allow comparison between methods that use different analytical approaches [ 10 ] [ 31 ]. Studies using combination of different prediction tools have identified deleterious mutations in genes involved in different biological processes, including, for example, cancer (breast cancer 1, early onset— BRCA1 gene) [ 32 ], STIL gene [ 33 ], Centromere-associated protein-E gene (CENP-E) [ 34 ], leukemia (c-abl oncogene 1— ABL1 gene) [ 35 ], lipoprotein metabolism (ATP-binding cassette transporter A1— ABCA1 gene) [ 36 ], cardiomyopathy (beta myosin heavy chain— MyH7 gene) [ 28 ], oxidative stress (superoxide dismutase 2— SOD2 gene) [ 37 ], amyotrophic lateral sclerosis (superoxide dismutase 1— SOD1 gene) [ 38 ], and melanogenesis (receptor tyrosine kinase— KIT gene [ 39 ], oculocutaneous albinism type 2— OCA2 —P protein gene [ 40 ], tyrosinase— TYR gene [ 41 ], and tyrosinase-related protein 1— TYRP1 gene [ 42 ]), resulting in the establishment of the mutations with the highest pathogenic prediction.…”