Telomeric G-quadruplexes have been a promising target for developing antitumor drugs with fewer side effects. The intracellular environment is usually in a state of molecular crowding. Studying the interaction mechanism among ligands and telomeric G-quadruplexes under crowded conditions is important for designing drugs that target telomeric G-quadruplexes. In the present study, the telomeric G-quadruplex Tel24 (TTAGGG)4 was found to fold into a conformational ensemble of parallel and (3 + 1) hybrid-2 conformations in solution with molecular crowding conditions created by PEG200. G-quadruplex-ligand 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl] acridinium methosulfate (RHPS4) preferentially stabilized the (3 + 1) hybrid-2 conformation and shifted the conformational ensemble equilibrium of Tel24 towards the hybrid conformation. We also found that the (3 + 1) hybrid-2 conformation of Tel24 was more likely to form as compared to the parallel conformation in the conformational ensemble of Tel24. Overall, this study provides new insights into the conformation of telomere G-quadruplexes and their interactions with ligands in a physiological environment.
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