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

Haldar, Susanta, Zhang, Yashu, Xia, Ying, Islam, Barira, Liu, Sisi, Gervasio, Francesco L., Mulholland, Adrian J., Waller, Zoë A.E., Wei, Dengguo and Haider, Shozeb (2022) Mechanistic Insights into the Ligand-Induced Unfolding of an RNA G-Quadruplex. Journal of the American Chemical Society, 144 (2). pp. 935-950. ISSN 0002-7863

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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.

Item Type:	Article
Additional Information:	Data availability statement: The unbiased simulation trajectories have been uploaded to zenodo (doi 10.5281/zenodo.5594466). Metadynamics simulation trajectories can be obtained from the authors upon request.
Uncontrolled Keywords:	catalysis,general chemistry,biochemistry,colloid and surface chemistry ,/dk/atira/pure/subjectarea/asjc/1500/1503
Faculty \ School:	Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
Related URLs:	https://www.scopus.com/pages/publication...
Depositing User:	LivePure Connector
Date Deposited:	29 Apr 2026 15:44
Last Modified:	29 Apr 2026 15:44
URI:	https://ueaeprints.uea.ac.uk/id/eprint/102836
DOI:	10.1021/jacs.1c11248

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