SOD1 in amyotrophic lateral sclerosis development – in silico analysis and molecular dynamics of A4F and A4V variants

• Published in: Journal of cellular biochemistry 2019-10, Vol.120 (10), p.17822-17830
• Main Authors: Da Silva, Aloma Nogueira Rebello, Pereira, Gabriel Rodrigues Coutinho, Moreira, Lorena Giannini Alves, Rocha, Catielly Ferreira, Mesquita, Joelma Freire
• Format: Article
• Language: English
• Subjects: A4V and A4F variants; Algorithms; Amyotrophic lateral sclerosis; Computer simulation; Drug development; Genetics; Molecular dynamics; molecular dynamics simulation; Motor neurons; Mutation; Neurodegenerative diseases; Neurological diseases; Nucleotides; Protein structure; Proteins; single‐nucleotide polymorphism; structural analysis; Structural stability; Structure-function relationships; Superoxide dismutase; superoxide dismutase‐1
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.29048

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by the selective loss of motor neurons. Approximately 5% to 10% of patients with ALS have a family history of the disease, and approximately 20% of familial amyotrophic lateral sclerosis (fALS) cases are associated with mutations in Cu/Zn superoxide dismutase (SOD1). In this study, we evaluated the structural and functional effects of human A4F and A4V SOD1 protein mutations. We performed an in silico analysis using prediction algorithms of nonsynonymous single‐nucleotide polymorphisms (nsSNPs) associated with the fALS development. Our structural conservation results show that the mutations analyzed (A4V and A4F) were in a highly conserved region. Molecular dynamics simulations using the Linux GROMACS package revealed how these mutations affect protein structure, protein stability, and aggregation. These results suggest that there might be an effect on the SOD1 function. Understanding the molecular basis of disease provides new insights useful for rational drug design and advancing our understanding of the ALS development. Manuscript provides the first structural modeling and in silico analysis of A4F and A4V mutations in superoxide dismutase‐1 (SOD1), a protein that plays a key role in oxidative stress and in amyotrophic lateral sclerosis development.