华中农业大学位灯国团队报道了配体诱导RNA G四链体去折叠的机制研究。相关研究成果发表在2022年1月6日出版的《美国化学会杂志》。

阳离子卟啉TMPyP4是一种成熟的DNA G-四链体（G4）结合配体，可通过多种结合模式稳定不同的拓扑结构。然而，TMPyP4对RNA G4结构既有稳定作用，也有失稳作用。介导RNA G4去折叠的结构机制尚不清楚。

该文中，研究人员报告了TMPyP4诱导的RNA G4去折叠机制，该机制由温和的元动力学（WT MetaD）和支持生物物理实验研究。模拟预测了TMPyP4通过沟槽束缚和顶面束缚构象相互作用的双态机制。TMPyP4在顶部四分体上的堆积动力学破坏了鸟嘌呤碱基之间的Hoogsteen H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。

附：英文原文

Title: Mechanistic Insights into the Ligand-Induced Unfolding of an RNA G-Quadruplex

Author: Susanta Haldar, Yashu Zhang, Ying Xia, Barira Islam, Sisi Liu, Francesco L. Gervasio, Adrian J. Mulholland, Zo A. E. Waller, Dengguo Wei, Shozeb Haider

Issue&Volume: January 6, 2022

Abstract: 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.

DOI: 10.1021/jacs.1c11248

Source: https://pubs.acs.org/doi/10.1021/jacs.1c11248