Dynamic properties of SOD1 mutants can predict survival time of patients carrying familial amyotrophic lateral sclerosis

Nikolay A. Alemasov, Nikita V. Ivanisenko, Sergey P. Medvedev, Suren M. Zakian, Nikolay A. Kolchanov, Vladimir A. Ivanisenko

    Результат исследования: Научные публикации в периодических изданияхстатья

    6 Цитирования (Scopus)

    Аннотация

    One of the reasons for the death of motor neurons of the brain and spinal cord in patients with amyotrophic lateral sclerosis is known to be formation of subcellular protein aggregates that are caused by mutations in the SOD1 gene. Patient survival time was earlier shown to have limiting correlation with thermostability change of SOD1 mutant forms of patients’ carriers. We hypothesized that aggregation of mutant SOD1 may occur not only due to the protein destabilization, but through formation of novel interatomic bonds which stabilize “pathogenic” conformations of the mutant as well. To estimate these effects in the present paper, we performed statistical analysis of occupancy of intramolecular hydrogen bonds, hydrogen bonds between the protein and water molecules, and water bridges with use of molecular dynamics simulation for 38 mutant SOD1 forms. Multiple regression model based on these kinds of bonds demonstrated correlation with patient survival time significantly better (R =.9, p-value < 10−11) than the thermostability of SOD1 mutants only. It was shown that the occupancy of intramolecular hydrogen bonds between amino acid residues is a key determinant (R =.89, p-value < 10−10) in predicting patients’ survival time.

    Язык оригиналаанглийский
    Страницы (с-по)645-656
    Число страниц12
    ЖурналJournal of Biomolecular Structure and Dynamics
    Том35
    Номер выпуска3
    DOI
    СостояниеОпубликовано - 17 фев 2017

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