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

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 associa...

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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
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Summary: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.
ISSN:0730-2312
1097-4644
DOI:10.1002/jcb.29048