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Modeling of mutant superoxide dismutase 1 octamers with cross-linked disulfide bonds

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Abstract

Mutant superoxide dismutase 1 (SOD1) may form cyclic structures due to its greater instability from aberrant demetallization and oxidation of cysteine bonds. This cyclic structure may allow SOD1 to form ion channels on membranes such as the mitochondrial membrane, causing imbalances in the concentration of intracellular ions as a potential mechanism for the progressive neuron death involved in amyotrophic lateral sclerosis (ALS). Using docking programs within modeling software, models of mutant SOD1 dimers and eventually ring oligomers were constructed based on known descriptions of such structures in addition to information on the orientation of the models associated with a membrane. The resulting structure consists of a ring of four demetallated mutant SOD1 dimers with cross-linked disulfide bonds. Stability of the octamer model was supported by the molecular dynamics simulations. Further analysis of the octamer model indicated that its inner- and outer-pore diameters were stable, matching the dimensions of known SOD1 ion channels.

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Authors and Affiliations

  1. REHS Program, San Diego Supercomputer Center, UC San Diego, La Jolla, CA, USA

    Aidan Zhang

  2. University of Bergen, Bergen, Norway

    Knut Teigen

  3. San Diego Supercomputer Center, UC San Diego, La Jolla, CA, USA

    Valentina L. Kouznetsova & Igor F. Tsigelny

  4. BiAna, La Jolla, CA, USA

    Valentina L. Kouznetsova & Igor F. Tsigelny

  5. Department of Neurosciences, UC San Diego, La Jolla, CA, USA

    Igor F. Tsigelny

Authors
  1. Aidan Zhang
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  2. Knut Teigen
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  3. Valentina L. Kouznetsova
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  4. Igor F. Tsigelny
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Contributions

Molecular modeling and writing of the article: AZ, interpretation of the results: AZ and VLK, molecular dynamics simulations: KT, modeling of dimers and revising of the article: IFT and VLK.

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Correspondence to Igor F. Tsigelny.

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Zhang, A., Teigen, K., Kouznetsova, V.L. et al. Modeling of mutant superoxide dismutase 1 octamers with cross-linked disulfide bonds. J Mol Model 28, 89 (2022). https://doi.org/10.1007/s00894-022-05072-4

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  • DOI: https://doi.org/10.1007/s00894-022-05072-4

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