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.
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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.
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