Reaction Coordinate and Thermodynamics of Base Flipping in RNA
Reaction Coordinate and Thermodynamics of Base Flipping in RNA
复制标题
DOI：
10.1021/acs.jctc.0c01199
复制
发表时间：
2021-02-17
影响因子：
5.5
通讯作者：
Vashisth, Harish
中科院分区：
文献类型：
--
作者：
Levintov, Lev;Paul, Sanjib;Vashisth, Harish
碱基翻转是核糖核酸（RNA）分子识别各种配体的关键生物物理事件。然而，RNA中碱基翻转的机制仍然知之甚少，部分原因是缺乏邻近碱基复杂重排的原子细节。在这项工作中，我们应用转换路径采样（TPS）方法来研究双链RNA（dsRNA）分子中的碱基翻转，已知该分子通过这种机制与RNA编辑酶相互作用。我们得到了一个合奏的1000过渡轨迹来描述基地翻转过程。我们使用似然最大化方法来确定由两个集体变量（CV）、与翻转碱基形成堆叠相互作用的核苷酸之间的距离和二面角组成的精细反应坐标（RC）。自由能分布预测沿着细化RC揭示了三个极小值，两个对应于初始和最终状态和一个亚稳态。我们认为，亚稳态可能代表了核磁共振研究中观察到的核碱基的摆动构象，通常被表征为翻转状态。反应轨迹的分析进一步揭示了碱基翻转与dsRNA茎环中的全局构象变化相耦合。
Base flipping is a key biophysical event involved in recognition of various ligands by ribonucleic acid (RNA) molecules. However, the mechanism of base flipping in RNA remains poorly understood, in part due to the lack of atomistic details on complex rearrangements in neighboring bases. In this work, we applied transition path sampling (TPS) methods to study base flipping in a double-stranded RNA (dsRNA) molecule that is known to interact with RNA-editing enzymes through this mechanism. We obtained an ensemble of 1000 transition trajectories to describe the base-flipping process. We used the likelihood maximization method to determine the refined reaction coordinate (RC) consisting of two collective variables (CVs), a distance and a dihedral angle between nucleotides that form stacking interactions with the flipping base. The free energy profile projected along the refined RC revealed three minima, two corresponding to the initial and final states and one for a metastable state. We suggest that the metastable state likely represents a wobbled conformation of nucleobases observed in NMR studies that is often characterized as the flipped state. The analyses of reactive trajectories further revealed that the base flipping is coupled to a global conformational change in a stem-loop of dsRNA.