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Российский физиологический журнал им. И.М. Сеченова, 2023, T. 109, № 12, стр. 1810-1831

Взаимодействие гликированного альбумина с рецептором конечных продуктов гликирования по данным молекулярного моделирования

Д. А. Белинская 1, *, Н. В. Гончаров 1, 2

1 Институт эволюционной физиологии и биохимии им. И.М. Сеченова РАН
Санкт-Петербург, Россия

2 НИИ гигиены, профпатологии и экологии человека
г.п. Кузьмоловский, Ленинградская обл., Россия

* E-mail: d_belinskaya@mail.ru

Поступила в редакцию 04.09.2023
После доработки 13.10.2023
Принята к публикации 16.10.2023

Аннотация

У больных сахарным диабетом (СД) накопление конечных продуктов гликирования (AGE – advanced glycation end products) ведет к воспалению и оксидативному стрессу посредством активации специфических рецепторов AGE (RAGE). Гликированный альбумин (gHSA) вносит существенный вклад в общий уровень AGE в организме и, как следствие, в патогенез диабета и сопутствующих заболеваний. Механизм взаимодействия gHSA с RAGE практически не изучен. Цель представленного исследования – методами молекулярного моделирования изучить связывание gHSA с RAGE, определить основные участки взаимодействия и структурные особенности сайтов гликирования, определяющие эффективность образования комплекса с RAGE. Методами молекулярного докинга и молекулярной динамики (МД) были сконструированы десять моделей gHSA, каждой модели соответствовал один модифицированный остаток лизина (карбоксиметил-лизин): Lys64, Lys73, Lys137, Lys233, Lys262, Lys317, Lys378, Lys525, Lys573, Lys574. Методом макромолекулярного докинга построены комплексы gHSA с V-доменом RAGE, методом МД изучена их стабильность. В построенных моделях gHSA карбоксильные группы гликированных Lys317 и Lys525 образуют внутримолекулярные солевые мостики с окружающими аминокислотами, в остальных случаях карбоксильные группы модифицированных лизинов свободны для взаимодействия с положительно заряженными аминокислотными остатками на поверхности RAGE. Согласно данным макромолекулярного докинга и последующей симуляции МД, самым эффективным с точки зрения прочности и специфичности является комплекс RAGE с gHSA, гликированным по Lys233. Специфические комплексы RAGE с gHSA, гликированным по Lys317 и Lys574, не образуются. Полученные данные о взаимодействии gHSA с RAGE помогут понять роль альбумина в патофизиологии СД и продвинуться на пути профилактики и создания эффективной терапии этого заболевания.

Ключевые слова: сахарный диабет, гликированный альбумин, карбоксиметил-лизин, рецептор конечных продуктов гликирования, молекулярное моделирование

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