Russian Journal of Biological Physics and Chemisrty Russian Journal of Biological Physics and Chemisrty АКТУАЛЬНЫЕ ВОПРОСЫ БИОЛОГИЧЕСКОЙ ФИЗИКИ И ХИМИИ 2499-9962 54041 МОЛЕКУЛЯРНАЯ БИОФИЗИКА И ФИЗИКА БИОМОЛЕКУЛ MOLECULAR BIOPHYSICS AND PHYSICS OF BIOMOLECULES МОЛЕКУЛЯРНАЯ БИОФИЗИКА И ФИЗИКА БИОМОЛЕКУЛ IN SILICO ESTIMATION OF THE MEMBRANE EFFECT ON THE DIMERIZATION OF TRANSMEMBRANE DOMAINS OF GLYCOPHORIN A ОЦЕНКА ВЛИЯНИЯ СРЕДЫ НА ДИМЕРИЗАЦИЮ ТРАНСМЕМБРАННЫХ ДОМЕНОВ ГЛИКОФОРИНА А В КОМПЬЮТЕРНОМ ЭКСПЕРИМЕНТЕ Кузнецов А С Kuznetsov A S andrej.kuznecov@phystech.edu Ефремов Р Г Efremov R G ФГБУН Институт биоорганической химии им. акад. М.М. Шемякина и Ю.А. Овчинникова РАН ru M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences ru ФГБУН Институт биоорганической химии им. акад. М.М. Шемякина и Ю.А. Овчинникова РАН; Национальный исследовательский университет Высшая школа экономики ru M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences; National Research University Higher School of Economics ru 25 06 2016 25 06 2016 1 1 250 254 20 06 2016 20 06 2016 https://rusjbpc.ru/en/nauka/article/54041/view

Разработан комплексный подход к изучению взаимного влияния белка и мембранной среды в процессе димеризации трансмембранных (ТМ) α-спиральных пептидов. В основе подхода - численное разложение профилей свободной энергии взаимодействия ТМ- спиралей на компоненты, соответствующие различным типам взаимодействий, и картирование пространственного распределения средней плотности липидов. Метод апробирован для ТМ-сегментов гликофорина А человека (GpA) и нескольких модельных пептидов. Показано, что липиды вносят значительный выгодный вклад в свободную энергию димеризации, в то время как образующиеся на интерфейсе мономеров контакты аминокислотных остатков могут, наоборот, быть невыгодными. Также на боковой поверхности ТМ-доменов GpA показано наличие сайтов связывания ацильных цепей молекул липидов. Таким образом, аминокислотная последовательность белка определяет и белок- белковые взаимодействия, и связывание липидов, что влияет на детальное распределение энергетических вкладов. При этом липидная мембрана может выступать в качестве непосредственного участника спонтанной ассоциации ТМ α-спиралей. Результаты данной работы могут быть использованы для рационального конструирования перспективных пептидных модуляторов, направленных на корректировку работы битопных мембранных белков, включая рецепторные тирозинкиназы.

Here we present a combined method to study mutual effects of a protein and a membrane upon the dimerization of transmembrane (TM) α-helical peptides. The approach is based on the numerical decomposition of dimerization free energy profiles for TM helices into components corresponding to different interaction types and on the mapping of the distribution of the average lipid density around the protein. The method was tested on the TM domains of human glycophorin A (GpA) and several model peptides. It is shown that lipids contribute significantly to a total free energy of dimerization, and the direct protein-protein contacts may be unfavorable. Also, we found some lipid acyl chains binding sides on the surface of TM domains of GpA. Thus, the amino acid sequence determines not only the protein- protein contacts during dimerization, but also the interactions with lipids, and that can determine the detailed balance between the free energy contributions. Lipid membrane can act as an active driving force in the process of TM helices association. The look rather promising for further rational design of peptide modulators aimed to interact with bitopic membrane proteins, including receptor tyrosine kinases.

 трансмембранные домены энергия ассоциации мембранные белки гликофорин А transmembrane domains dimerization energy membrane proteins glycophorin A

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