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

Abstract

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.

Bridging the Bridging Imidazolate in the Bimetallic Center of the Cu/Zn SOD1 and ALS

“…Given this caveat, we opted for the second ground state with a reduced Cu-center and a protonated H63 which can be easily defined by conventional force fields. Previous MD studies of SOD1 either did not disclose any details for the metal center parameters (Srinivasan and Rajasekaran, 2017;Pereira et al, 2021) or similar to this study modeled the SOD1 from the second ES complex (Mera-Adasme et al, 2013).…”

“…MD simulations present alternative methodologies that can access the dynamics of macro-molecules (Adler-Abramovich et al, 2012;Mera-Adasme et al, 2013). Specifically, many studies have used MD simulations to investigate structural mechanism behind SOD1-mediated ALS toxicity (Banci et al, 1992;Strange et al, 2007;Srinivasan and Rajasekaran, 2017;Pereira et al, 2021). To elaborate the impact of the hypothetical SOD1 mutations on the dimer dynamics, we have employed classical molecular dynamics simulations to study six SOD1 variants.…”

Molecular dynamics and protein frustration analysis of human fused in Sarcoma protein variants in Amyotrophic Lateral Sclerosis type 6: An In Silico approach

“…MD simulations and functional predictions have been proven to be valuable for uncovering the effects of single mutations in proteins [ 68 ]. In addition to the methods presented in this paper, other powerful in silico approaches for the study of missense mutations are also available and worth mentioning.…”

“…e . opening, closing, and flexing) from small irrelevant local fluctuations, thus, providing detailed information on conformational dynamics [ 68 ].…”

“…We used the methodology previously described by our group [ 13 – 15 ] to analyze the effects that mutations R521C, R521H, and P525L have over the human FUS protein.…”