Molecular mechanisms underlying the impact of mutations in SOD1 on its conformational properties associated with amyotrophic lateral sclerosis as revealed with molecular modelling

Abstract

BackgroundSo far, little is known about the molecular mechanisms of amyotrophic lateral sclerosis onset and progression caused by SOD1 mutations. One of the hypotheses is based on SOD1 misfolding resulting from mutations and subsequent deposition of its cytotoxic aggregates. This hypothesis is complicated by the fact that known SOD1 mutations of similar clinical effect could be distributed over the whole protein structure.ResultsIn this work, a measure of hydrogen bond stability in conformational states was studied with elastic network analysis of 35 SOD1 mutants. Twenty-eight hydrogen bonds were detected in nine of 35 mutants with their stability being significantly different from that with the wild-type. These hydrogen bonds were formed by the amino acid residues known from the literature to be located in contact between SOD1 aggregates. Additionally, residues disposed between copper binding sites of both protein subunits were found from the models to form a stiff core, which can be involved in mechanical impulse transduction between these active centres.ConclusionsThe modelling highlights that both stability of the copper binding site and stability of the dimer can play an important role in ALS progression.Electronic supplementary materialThe online version of this article (10.1186/s12900-018-0080-9) contains supplementary material, which is available to authorized users.

Structural Determination, Biological Function, and Molecular Modelling Studies of Sulfoaildenafil Adulterated in Herbal Dietary Supplement

“…Although a lower estimated value of the binding affinity indicates stronger interactions of the protein–ligand complex, the small binding energy difference among these complexes is only 0.5~1 kcal mol −1 . The interactions of each drug with the potential site of PDE5 were mediated by the hydrophilic/hydrophobic interactions as supported by the findings in previous studies [ 23 , 24 , 25 ]. As a combined result of experimental study, the subtle differences that were found in the estimated binding energy have led us to further investigate the obtained complex by a comparison between sildenafil and sulfoaildenafil using MD simulations.…”

“…Here, the molecular docking approach was firstly performed to predict the bioactive binding modes and affinity of the PDE5 inhibitor on the target protein. It should be noted that all models of the well-known PDE5 inhibitors were found to occupy part of the Q pocket (Gln817 and Leu804) at the immediate vicinity of the binding site with the pyrazolopyrimidinone ring of the inhibitors, suggesting the above-mentioned drugs can be accommodated in PDE5 protein and also present PDE5 inhibitor activity [ 24 ]. The binding modes were observed at the same site with slightly different binding conformations compared with the sildenafil as a common drug used as a PDE5 inhibitor ( Figure S5, Supplementary Information ).…”

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

“…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 ].…”

Superoxide Dismutase 1 in Health and Disease: How a Frontline Antioxidant Becomes Neurotoxic

“…Multiple studies conducted under physiological conditions (temperature, pH, and protein concentration) have identified exacerbated instability within the dimer interface [105a, 109] and/or the electrostatic loop [35, 110] of the holo and apo proteins of numerous MBR and WTL mutants. Seventy out of seventy‐five investigated SOD1 mutations (MBR and WTL) result in dimer instability and/or increased dimer dissociation in silico, [111] resulting from widespread disruption of hydrogen bonding networks in β‐strands 1, 2, 7, and 8, the dimer interface, and the electrostatic, disulfide, and Greek key loops [39b] . The degree of destabilisation does, however, vary considerably between individual mutants.…”