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

Silva, Aloma Nogueira Rebello Da; Pereira, Gabriel Rodrigues Coutinho; Moreira, Lorena Giannini Alves; Rocha, Catielly F; Mesquita, Joelma Freire De

doi:10.1002/jcb.29048

Cited by 14 publications

(9 citation statements)

References 51 publications

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“…As predicted by ConSurf ( S2 Fig), the amino-acid substitution A4V and H46R occur at known conserved regions of SOD1 [21,35,87]. Although our results indicated that the variant I113T occurs in a variable position, this amino-acid is evolutionarily conserved in mammals [88].…”

Section: Plos Onesupporting

confidence: 62%

“…This mutation was previously found in an fALS patient, but the characterization of its effects has not yet been performed [73]. The amino-acid substitution P66R occurs at the metal-binding loop of SOD1 [74], which could hinder binding, preventing CCS action [75][76][77].…”

Section: Plos Onementioning

confidence: 99%

“…The computational approach has become widely used to characterize the effects of mutations in proteins and to identify potentially deleterious mutations, particularly because of its relatively high cost/efficiency and accuracy [19]. We applied computational predictions to the study of SOD1 protein variants following the methodology previously established by our group [16,[19][20][21][22]. This work aims to characterize the effects of these variants on the SOD1 structure, which could assist the design of future experiments and provide relevant information on the molecular mechanism of pathology that may lead to improvements in existing treatments for ALS [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis

2021

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Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disorder, with a significant social and economic burden. ALS remains incurable, and the only drugs approved for its treatments confers a survival benefit of a few months for the patients. Missense mutations in superoxide dismutase 1 (SOD1), a major cytoplasmic antioxidant enzyme, has been associated with ALS development, accounting for 23% of its familial cases and 7% of all sporadic cases. This work aims to characterize in silico the structural and functional effects of SOD1 protein variants. Missense mutations in SOD1 were compiled from the literature and databases. Twelve algorithms were used to predict the functional and stability effects of these mutations. ConSurf was used to estimate the evolutionary conservation of SOD1 amino-acids. GROMACS was used to perform molecular dynamics (MD) simulations of SOD1 wild-type and variants A4V, D90A, H46R, and I113T, which account for approximately half of all ALS-SOD1 cases in the United States, Europe, Japan, and United Kingdom, respectively. 233 missense mutations in SOD1 protein were compiled from the databases and literature consulted. The predictive analyses pointed to an elevated rate of deleterious and destabilizing predictions for the analyzed variants, indicating their harmful effects. The ConSurf analysis suggested that mutations in SOD1 mainly affect conserved and possibly functionally essential amino acids. The MD analyses pointed to flexibility and essential dynamics alterations at the electrostatic and metal-binding loops of variants A4V, D90A, H46R, and I113T that could lead to aberrant interactions triggering toxic protein aggregation. These alterations may have harmful implications for SOD1 and explain their association with ALS. Understanding the effects of SOD1 mutations on protein structure and function facilitates the design of further experiments and provides relevant information on the molecular mechanism of pathology, which may contribute to improvements in existing treatments for ALS.

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Section: Plos Onesupporting

confidence: 62%

Section: Plos Onementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis

2021

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“…Furthermore, we developed a database, SNPMOL (http://www.snpmol.org/) [40], to host the results presented in this paper. The database is human-curated and freely available for biologists and clinicians to exploit the functional and structural effects of the 46 TPH2 variants that we compiled from the literature.…”

Section: Plos Onementioning

confidence: 99%

In silico analysis of the tryptophan hydroxylase 2 (TPH2) protein variants related to psychiatric disorders

et al. 2020

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The tryptophan hydroxylase 2 (TPH2) enzyme catalyzes the first step of serotonin biosynthesis. Serotonin is known for its role in several homeostatic systems related to sleep, mood, and food intake. As the reaction catalyzed by TPH2 is the rate-limiting step of serotonin biosynthesis, mutations in TPH2 have been associated with several psychiatric disorders (PD). This work undertakes an in silico analysis of the effects of genetic mutations in the human TPH2 protein. Ten algorithms were used to predict the functional and stability effects of the TPH2 mutations. ConSurf was used to estimate the evolutionary conservation of TPH2 amino acids. GROMACS was used to perform molecular dynamics (MD) simulations of TPH2 WT and P260S, R303W, and R441H, which had already been associated with the development of PD. Forty-six TPH2 variants were compiled from the literature. Among the analyzed variants, those occurring at the catalytic domain were shown to be more damaging to protein structure and function. The ConSurf analysis indicated that the mutations affecting the catalytic domain were also more conserved throughout evolution. The variants S364K and S383F were predicted to be deleterious by all the functional algorithms used and occurred at conserved positions, suggesting that they might be deleterious. The MD analyses indicate that the mutations P206S, R303W, and R441H affect TPH2 flexibility and essential mobility at the catalytic and oligomerization domains. The variants P206S, R303W, and R441H also exhibited alterations in dimer binding affinity and stability throughout the simulations. Thus, these mutations may impair TPH2 functional interactions and, consequently, its function, leading to the development of PD. Furthermore, we developed a database, SNPMOL (http://www.snpmol.org/), containing the results presented in this paper. Understanding the effects of TPH2 mutations on protein structure and function may lead to improvements in existing treatments for PD and facilitate the design of further experiments.

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“…Prediction of the effects of variants by computational algorithms -Computational simulations were applied to study NAT2 protein variants following the previously established methodology. (23,24,25) The wild-type NAT2 protein sequence was retrieved from the UniProt database (UniProt ID: P11245). (26) The functional effects of NAT2 missense mutations were predicted using the PredictSNP, a consensus method that combines the evaluation of six prediction algorithms: MAPP, PhD-SNP, PolyPhen-1, PolyPhen-2, SIFT, and SNAP.…”

Section: Study Participants and Settingsmentioning

confidence: 99%

Homozygotes NAT2*5B slow acetylators are highly associated with hepatotoxicity induced by anti-tuberculosis drugs

El-Jaick

Ribeiro-Alves

Soares

et al. 2022

Mem. Inst. Oswaldo Cruz

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

Cited by 14 publications

References 51 publications

Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis

Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis

In silico analysis of the tryptophan hydroxylase 2 (TPH2) protein variants related to psychiatric disorders

Homozygotes NAT2*5B slow acetylators are highly associated with hepatotoxicity induced by anti-tuberculosis drugs

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