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

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-DC₃ 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.