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

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

Research output: Contribution to journalArticle (Academic Journal)peer-review

28 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)935-950
Number of pages16
JournalJournal of the American Chemical Society
Issue number2
Publication statusPublished - 19 Jan 2022

Bibliographical note

Funding Information:
D.G.W. is supported by the National Natural Science Foundation of China (21732002, 22077043, 31672558). A.J.M. and S.H. would like to acknowledge the EPSRC grants for this study (EP/N024117/1 and EP/M022609/1). S.H. would like to thank Dr. Gary N. Parkinson for critical reading of the manuscript. D.G.W would like to thank Chen Dong and Qi Zhou.

Publisher Copyright:
© 2022 American Chemical Society


  • Cations/chemistry
  • G-Quadruplexes
  • Hydrogen Bonding
  • Intercalating Agents/chemistry
  • Ligands
  • Molecular Dynamics Simulation
  • Nucleic Acid Conformation
  • Porphyrins/chemistry
  • Thermodynamics


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