ArticleThe journal of physical chemistry letters2019
An Allosteric Pathway in Copper, Zinc Superoxide Dismutase Unravels the Molecular Mechanism of the G93A Amyotrophic Lateral Sclerosis-Linked Mutation.
Article in The journal of physical chemistry letters, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed.
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- Bridging Scales: Coarse-Grained Protein Models in Computational Biology.Advances in experimental medicine and biology · 2026Review
- The structure, redox chemistry and motor neuron toxicity of heterodimeric zinc-deficient SOD1-implications for the toxic gain of function observed in ALS.Neurobiology of disease · 2025Article
- Pathological Disulfide Bond Crosslinking: Molecular Insights into Amyloidogenesis and Diseases Progression.Chembiochem : a European journal of chemical biology · 2025Review
- The structure, redox chemistry and motor neuron toxicity of heterodimeric zinc-deficient SOD1-Implications for the toxic gain of function observed in ALS.bioRxiv : the preprint server for biology · 2025Article
- GōMartini 3: From large conformational changes in proteins to environmental bias corrections.Nature communications · 2025Article
- Modulation of ZnT-1 by Let7a unveils a therapeutic potential in amyotrophic lateral sclerosis.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- Theoretical evaluation of a bulkyRSC advances · 2025Article
- Martini 3 OliGo̅mers: A Scalable Approach for Multimers and Fibrils in GROMACS.Journal of chemical theory and computation · 2024Article
- Exploring the Ligand Binding and Conformational Dynamics of the Substrate-Binding Domain 1 of the ABC Transporter GlnPQ.The journal of physical chemistry. B · 2024Article
- Protein aggregation and therapeutic strategies in SOD1- and TDP-43- linked ALS.Frontiers in molecular biosciences · 2024Review
- Localization of the tubby domain, a PI(4,5)P2 biosensor, to E-Syt3-rich endoplasmic reticulum-plasma membrane junctions.Journal of cell science · 2023Article
- A Zn-dependent structural transition of SOD1 modulates its ability to undergo phase separation.The EMBO journal · 2023Article
- May the force be with you: The role of hyper-mechanostability of the bone sialoprotein binding protein during early stages ofFrontiers in chemistry · 2023Article
- Molecular dynamics analysis of superoxide dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression.Computational and structural biotechnology journal · 2023Article
- Molecular dynamics simulation of an entire cell.Frontiers in chemistry · 2023Article
- Martini 3 Coarse-Grained Force Field for Carbohydrates.Journal of chemical theory and computation · 2022Article
- Application of Computational Biology and Artificial Intelligence in Drug Design.International journal of molecular sciences · 2022Review
- Two cooperative binding sites sensitize PI(4,5)PScience advances · 2022Article
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Authors and funding
4 authors.
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Abstract
Several different mutations of the protein copper, zinc superoxide dismutase (SOD1) produce the neurodegenerative disorder amyotrophic lateral sclerosis (ALS). The molecular mechanism by which the diverse mutations converge to a similar pathology is currently unknown. The electrostatic loop (EL) of SOD1 is known to be affected in all of the studied ALS-linked mutations of SOD1. In this work, we employ a multiscale simulation approach to show that this perturbation corresponds to an increased probability of the EL detaching from its native position, exposing the metal site of the protein to water. From extensive atomistic and coarse-grained molecular dynamics (MD) simulations, we identify an allosteric pathway that explains the action of the distant G93A mutation on the EL. Finally, we employ quantum mechanics/molecular mechanics MD simulations to show that the opening of the EL decreases the Zn(II) affinity of the protein. As the loss of Zn(II) is at the center of several proposed pathogenic mechanisms in SOD1-linked ALS, the structural effect identified here not only is in agreement with the experimental data but also places the opening of the electrostatic loop as the possible main pathogenic effect for a significant number of ALS-linked SOD1 mutations.
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