Role of conformational heterogeneity in ligand recognition by viral RNA molecules
Role of conformational heterogeneity in ligand recognition by viral RNA molecules
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DOI：
10.1039/d1cp00679g
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发表时间：
2021-04-01
影响因子：
3.3
通讯作者：
Vashisth，Harish
中科院分区：
文献类型：
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作者：
Levintov，Lev;Vashisth，Harish
众所周知，核糖核酸(RNA)分子会在各种环境刺激下发生构象变化，包括温度、pH和配体。特别是，病毒RNA分子是构象适应性分子的一个关键例子，这些分子已经进化成在许多功能构象之间切换。来自1型人类免疫缺陷病毒(HIV-1)的反式激活反应元件(TAR)RNA是一种病毒RNA分子，由于其在病毒复制过程中的作用，越来越多地被用作潜在的治疗靶点。在这项工作中，我们通过27个不同结构的显式溶剂分子动力学(MD)模拟研究了TAR RNA在apo和配位状态下的动力学。我们确定TAR RNA结构在配体结合上显着稳定，特别是其两个螺旋的波动减少。这种刚性还与凸起核苷酸翻转的减少有关，在没有配体的情况下，观察到凸起核苷酸的翻转更频繁。我们发现，在去除配体时，最初截然不同的TAR RNA结构收敛到类似的构象。我们还报道了未连接的TAR结构中的构象动力学导致了能够容纳不同大小的配体的结合口袋的形成。
Ribonucleic acid (RNA) molecules are known to undergo conformational changes in response to various environmental stimuli including temperature, pH, and ligands. In particular, viral RNA molecules are a key example of conformationally adapting molecules that have evolved to switch between many functional conformations. The transactivation response element (TAR) RNA from the type-1 human immunodeficiency virus (HIV-1) is a viral RNA molecule that is being increasingly explored as a potential therapeutic target due to its role in the viral replication process. In this work, we have studied the dynamics in TAR RNA in apo and liganded states by performing explicit-solvent molecular dynamics (MD) simulations initiated with 27 distinct structures. We determined that the TAR RNA structure is significantly stabilized on ligand binding with especially decreased fluctuations in its two helices. This rigidity is further coupled with the decreased flipping of bulge nucleotides, which were observed to flip more frequently in the absence of ligands. We found that initially-distinct structures of TAR RNA converged to similar conformations on removing ligands. We also report that conformational dynamics in unliganded TAR structures leads to the formation of binding pockets capable of accommodating ligands of various sizes.