| Autor: |
Susanta Haldar, Yashu Zhang, Ying Xia, Barira Islam, Sisi Liu, Francesco L. Gervasio, Adrian J. Mulholland, Zoë A. E. Waller, Dengguo Wei, Shozeb Haider |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Journal of the American Chemical Society. 144(2) |
| ISSN: |
1520-5126 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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