vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RASvavilov-322Research ArticleСтатьиArticlesСТРУКТУРНЫЕ И ДИНАМИЧЕСКИЕ ОСОБЕННОСТИ МУТАНТОВ БЕЛКА SOD1, АССОЦИИРОВАННЫХ С БОКОВЫМ АМИОТРОФИЧЕСКИМ СКЛЕРОЗОМSTRUCTURAL AND DYNAMIC PROPERTIES OF MUTANTS OF THE SOD1 PROTEIN ASSOCIATED WITH AMYOTROPHIC LATERAL SCLEROSISАлемасовН. А.AlemasovN. A.alemasov@bionet.nsc.ruИванисенкоН. В.IvanisenkoN. V.alemasov@bionet.nsc.ruИванисенкоВ. А.IvanisenkoV. A.alemasov@bionet.nsc.ruФедеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук», Новосибирск, РоссияРоссияInstitute of Cytology and Genetics SB RAS, Novosibirsk, RussiaRussian Federation201422012015184/2920927Copyright © Алемасов Н.А., Иванисенко Н.В., Иванисенко В.А., 20152015Алемасов Н.А., Иванисенко Н.В., Иванисенко В.А.Alemasov N.A., Ivanisenko N.V., Ivanisenko V.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/322

Одной из причин гибели нейронов головного и спинного мозга при заболевании боковым амиотрофическим склерозом является образование внутриклеточных белковых агрегатов, вызванных мутациями в гене SOD1. Ранее показано, что продолжительность жизни пациентов отрицательно коррелирует с термостабильностью мутантных форм белка SOD1, носителями которых они были. В настоящей работе сделано предположение, что усиливать агрегацию мутантов SOD1 может не только дестабилизация структуры белка за счет разрушения водородных связей, но также возникновение новых водородных связей, стабилизирующих патогенную конформацию мутанта. Методом молекулярной динамики оценено время существования водородных связей в белке. Установлено, что корреляция этой оценки с продолжительностью жизни пациентов (R = 0,89, p < 0,00001) оказалась существенно сильнее корреляции, полученной ранее на основе анализа термостабильности мутантов.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which affects motor neurons in the brain and spinal cord and leads to patients’ death. One of the causes of motor neuron degeneration and death is the formation of intracellular protein aggregates formed by a mutant SOD1 protein. Recently, it has been shown that the survival time of ALS patients with specific mutation in SOD1 gene inversely correlates with thermodynamic stability of the SOD1 mutant protein. In the present paper, we hypothesize that mutant SOD1 aggregation can be facilitated by not only destabilization due to hydrogen bonds disruption but also by formation of new hydrogen bonds, which can stabilize intermediate “pathogenic” conformations of the mutant SOD1 protein. Molecular dynamics simulations were conducted to estimate frequencies of hydrogen bond occurrence in the protein structure. It was shown that the regression model based on frequencies of hydrogen bond occurrence significantly better correlated with patients’ survival time (R = 0.89, p < 0.00001) than the estimation based on thermodynamic stability analysis of mutant SOD1 proteins.

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The authors declare that there are no conflicts of interest present.