Exploring the modulation of the complex folding landscape of Human Telomeric DNA by low molecular weight ligands

Telomeric DNA forms G-quadruplex (G4) structures. G4s are crucial for genomic stability and therapeutic targeting. Using time-resolved NMR and CD spectroscopies, we investigated how the ligand Phen-DC3 modulates the folding of the human telomeric repeat 23TAG DNA sequence into G4. 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.