Exploring the Modulation of the Complex Folding Landscape of Human Telomeric DNA by a Low Molecular Weight Ligand

Abstract Telomeric DNA forms G‐quadruplex (G4) structures. These G4 structures are crucial for genomic stability and therapeutic targeting. Using time‐resolved NMR and CD spectroscopy, we investigated how the ligand Phen‐DC 3 modulates the folding of the human telomeric repeat 23TAG DNA. The kinetics are modulated by the ligand and by the presence of potassium cations (K + ). Ligand binding to G4 occurs via a triphasic process with fast and slow phases. Notably, for the G4 structure in the presence of K + , the slow rate is ten times slower than without K + . These findings offer key insights into the modulation of the complex folding landscape of G4s by ligands, advancing our understanding of G4‐ligand interactions for potential therapeutic applications.