Computer analysis of the relation between hydrogen bond stability in SOD1 mutants and the survival time of amyotrophic lateral sclerosis patients

Alemasov, Nikolay A.; Timofeev, V. S.; Ivanisenko, Nikita V.; Kolchanov, Nikolay А.; Иванисенко, В. А.

doi:10.1016/j.jmgm.2021.108026

Cited by 6 publications

(2 citation statements)

References 48 publications

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“…This is a very interesting observation, despite acting very similar to the wt-SOD1 on an atomic level the A4V variant manifests itself as a fast-progressing form of ALS. Previous studies have pointed out that the pathogenic mutations in SOD1 might alter the protein hydrogen bonds and promote the formation of new ones which can increase the probability of misfolding and aggregation in SOD1 [42,43]. Our results complement these by showing that apart from A4V, SOD1 variants generally form fewer hydrogen bonds which might affect the protein stability and favour misfolding.…”

Section: Discussionsupporting

confidence: 84%

Molecular dynamics analysis of Superoxide Dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression

Kalia

Miotto

Ness

et al. 2022

Preprint

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Mutations in the superoxide dismutase 1 (SOD1) gene are the second most common known cause of ALS. SOD1 variants express high phenotypic variability and over 200 have been reported in people with ALS. Investigating how different SOD1 variants affect the protein dynamics might help in understanding their pathogenic mechanism and explaining their heterogeneous clinical presentation. It was previously proposed that variants can be broadly classified in two groups, "wild-type like" (WTL) and "metal binding region" (MBR) variants, based on their structural location and biophysical properties. MBR variants are associated with a loss of SOD1 enzymatic activity. In this study we used molecular dynamics and large clinical datasets to characterise the differences in the structural and dynamic behaviour of WTL and MBR variants with respect to the wild-type SOD1, and how such differences influence the ALS clinical phenotype. Our study identified marked structural differences, some of which are observed in both variant groups, while others are group specific. Moreover, applying graph theory to a network representation of the proteins, we identified differences in the intramolecular contacts of the two classes of variants. Finally, collecting clinical data of approximately 500 SOD1 ALS patients carrying variants from both classes, we showed that the survival time of patients carrying an MBR variant is generally longer (~6 years median difference, p < 0.001) with respect to patients with a WTL variant. In conclusion, our study highlights key differences in the dynamic behaviour of the WTL and MBR SOD1 variants, and wild-type SOD1 at an atomic and molecular level. We identified interesting structural features that could be further investigated to explain the associated phenotypic variability. Our results support the hypothesis of a decoupling between mechanisms of onset and progression of SOD1 ALS, and an involvement of loss-of-function of SOD1 with the disease progression.

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Section: Discussionsupporting

confidence: 84%

Molecular dynamics analysis of Superoxide Dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression

Kalia

Miotto

Ness

et al. 2022

Preprint

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“…Next, DFT method with the hybrid functional B3LYP (Gaussian 09 software) was used to improve the structure of the ligands (Maldonado-Rojas and Olivero-Verbel 2011; Maldonado-Rojas et al 2016; Mercado-camargo et al 2020). The protein's 3D crystallographic structure was optimized by adding missing amino acids using the PDBFixer Anaconda application (Alemasov et al 2022); it was subsequently improved by getting rid of water molecules and co-crystallized substructures (ligands and ions), followed by energy minimization in the UCSF Chimera program using 1000 steps of steepest descent followed by 500 steps of conjugated gradient algorithms (Maldonado-Rojas et al Molecular docking was performed in AutoDock Vina via shell commands. For this, the spatial dimensions of the cube (gird) were established based on the reported bibliographic information regarding the active site of selected protein using Auto dock tools.…”

Section: Evaluation Of the Promising Activity Of Polyphenols Against Scamentioning

confidence: 99%

Identification of proinflammatory pathways and promising bioactive polyphenols for the treatment of sickle cell anemia by in silico study and network pharmacology

Pérez,

Lázaro,

Puentes

et al. 2024

Preprint

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Sickle cell anemia (SCA) is an autosomal recessive Mendelian trait characterized by symptoms that include acute and chronic pain, chest syndrome, pulmonary hypertension, stroke, kidney disease, and vaso-occlusive crises (VOCs), all of which worsen with age; VOCs are the leading cause of hospitalization and premature death in SCA patients. Currently, despite the existence of treatments for SCA, the negative consequences of VOCs’ chronic inflammatory state demand the exploration of alternative methods of control. For this reason, the goal of this research was to find novel pathways and promising bioactive polyphenols for the treatment of SCA using a combination of network pharmacology and in silico approaches; due to polyphenols, they have shown widely reported anti-inflammatory properties. Initially, hub genes associated with inflammatory processes in SCA were identified by extracting differentially expressed genes (DEGs) from a publicly available GEO dataset (GSE53441), followed by their validation through system biology analysis, Polyphenols with anti-inflammatory activity were selected from natural product databases; finally, molecular docking and dynamics were performed with the polyphenols and the key protein derived from the selected hub genes. As a result, 10 genes associated with the Type I interferon (IFN-I) pathway in SCA were identified (MX1, FIT1, IFIT3, STAT1, ISG15, GBP1, OAS1, OAS2, OAS3, and RSAD); among them, STAT1 was selected as a central hub gene by regulating the expression of the rest. Docking and dynamics studies showed good binding energies among STAT1 and the fifteen polyphenolic extracted compounds, with quercetin, diosmetin, and fisetin showing the lowest binding energies. Identified flavonoids have been described in the past as compounds having anti-inflammatory and antioxidant features, as well as possible alternatives for SCA treatment.

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Molecular dynamics analysis of superoxide dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression

Kalia,

Miotto,

Ness

et al. 2023

Computational and Structural Biotechnology Journal

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Computer analysis of the relation between hydrogen bond stability in SOD1 mutants and the survival time of amyotrophic lateral sclerosis patients

Cited by 6 publications

References 48 publications

Molecular dynamics analysis of Superoxide Dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression

Molecular dynamics analysis of Superoxide Dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression

Identification of proinflammatory pathways and promising bioactive polyphenols for the treatment of sickle cell anemia by in silico study and network pharmacology

Molecular dynamics analysis of superoxide dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression

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