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

Haldar, Susanta; Zhang, Yashu; Xia, Ying; Islam, Barira; Liu, Sisi; Gervasio, FL; Mulholland, AJ; ... Haider, S; + view all (2022) Mechanistic Insights into the Ligand-Induced Unfolding of an RNA G-Quadruplex. Journal of the American Chemical Society , 144 (2) pp. 935-950. 10.1021/jacs.1c11248. Green open access

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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.

Type: Article
Title: Mechanistic Insights into the Ligand-Induced Unfolding of an RNA G-Quadruplex
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/jacs.1c11248
Publisher version: https://doi.org/10.1021/jacs.1c11248
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
UCL > Provost and Vice Provost Offices > UCL BEAMS
URI: https://discovery.ucl.ac.uk/id/eprint/10142961
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