Mechanistic Insights into the Ligand-Induced Unfolding of an RNA G-Quadruplex
Mechanistic Insights into the Ligand-Induced Unfolding of an RNA G-Quadruplex
复制标题
配体诱导的 RNA G 四链体展开的机制见解
DOI：
10.1021/jacs.1c11248
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发表时间：
2022-01-06
影响因子：
15
通讯作者：
Haider, Shozeb
中科院分区：
文献类型：
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作者：
Haldar, Susanta;Zhang, Yashu;Haider, Shozeb
阳离子卟啉TMPyP4是一种成熟的DNA g -四重体（G4）结合配体，可以通过多种结合模式稳定不同的拓扑结构。然而，TMPyP4可以对RNA G4结构具有稳定和不稳定的作用。介导RNA G4展开的结构机制尚不清楚。在这里，我们报告了tmpyp4诱导的RNA G4展开机制，通过well-tempered metad动力学（WT-MetaD）和支持的生物物理实验研究。模拟预测了TMPyP4通过凹槽结合和顶面结合构象的两态相互作用机制。TMPyP4在顶部四分体上堆叠的动态破坏了鸟嘌呤碱基之间的Hoogsteen氢键，导致TMPyP4从顶部到底部连续插入g四分体。结果揭示了计算方法和实验方法之间的显著相关性，并验证了WT-MetaD模拟是研究RNA g4配体相互作用的有力工具。
The cationic porphyrin TMPyP4 is a well-established DNA G-quadruplex (G4) binding ligand that can stabilize different topologies via multiple binding modes. However, TMPyP4 can have both a stabilizing and destabilizing effect on RNA G4 structures. The structural mechanisms that mediate RNA G4 unfolding remain unknown. Here, we report on the TMPyP4-induced RNA G4 unfolding mechanism studied by well-tempered metadynamics (WT-MetaD) with supporting biophysical experiments. The simulations predict a two-state mechanism of TMPyP4 interaction via a groove-bound and a top-face-bound conformation. The dynamics of TMPyP4 stacking on the top tetrad disrupts Hoogsteen H-bonds between guanine bases, resulting in the consecutive TMPyP4 intercalation from top-to-bottom G-tetrads. The results reveal a striking correlation between computational and experimental approaches and validate WT-MetaD simulations as a powerful tool for studying RNA G4-ligand interactions.