Молекулярная биология, 2021, T. 55, № 6, стр. 1030-1044

Расчет энергии формирования дуплексов РНК/РНК и ДНК/РНК на основании метода молекулярной динамики

В. М. Голышев ab, Д. В. Пышный ab, А. А. Ломзов ab*

a Институт химической биологии и фундаментальной медицины Сибирского отеления Российской академии наук
630090 Новосибирск, Россия

b Новосибирский государственный университет
630090 Новосибирск, Россия

* E-mail: lomzov@niboch.nsc.ru

Поступила в редакцию 07.03.2021
После доработки 21.05.2021
Принята к публикации 21.05.2021

Аннотация

Создание подходов прогностического расчета гибридизационных свойств нуклеиновых кислот (НК), а также различных классов их производных считается фундаментом для рационального дизайна конструкций на их основе. Современные достижения в области методов компьютерного моделирования свидетельствуют о возможности таких вычислений. В работе впервые проанализирована возможность расчета энергии формирования ДНК/РНК- и РНК/РНК-дуплексов на примере представительных наборов комплексов (65 и 75 комплексов соответственно). Мы использовали метод классической молекулярной динамики (МД), методы MMPBSA или MMGBSA для расчета энтальпийной (ΔH°) составляющей и квазигармоническое приближение (Q-Harm) или метод анализа нормальных мод колебаний (NMA) для расчета энтропийной (ΔS°) составляющей энергии Гиббса ($\Delta G_{{37}}^{^\circ }$) образования НК-комплексов. Показано, что, используя метод MMGBSA при анализе МД-траектории только НК-дуплекса с учетом эмпирической линейной аппроксимации, можно рассчитывать энтальпию формирования ДНК, РНК и гибридных комплексов различной длины и GC-состава с точностью 8.6%. В рамках каждого типа комплексов комбинация достаточно производительных методов MMGBSA и Q-Harm, в применении к траектории только бимолекулярного комплекса, позволяет рассчитать величину $\Delta G_{{37}}^{^\circ }$ образования дуплекса с достоверностью 10%. Высокая точность прогностического расчета для разных типов природных комплексов (ДНК/ДНК, ДНК/РНК и РНК/РНК) указывает на большую вероятность распространения рассмотренного подхода на аналоги и производные НК. Это в перспективе даст принципиальную возможность перейти к рациональному дизайну новых типов НК-направленных сиквенсспецифических соединений.

Ключевые слова: термическая стабильность, гибридизация, молекулярная динамика, ДНК/РНК, РНК/РНК, дуплексы, MMPBSA, MMGBSA, олигонуклеотиды

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