Metal ions modulate the conformation and stability of a G-quadruplex with or without a small-molecule ligand

Small-molecule ligands for stabilizing the G-quadruplex in telomeres are promising chemotherapeutic agents. Despite extensive research, few G-quadruplex-stabilizing ligands have been clinically approved to date. We hypothesized that metal ions may be able to interfere with the ligand-mediated stabilization of the G-quadruplex. Here we found that several metal ions could interfere with the Na⁺-induced G-quadruplex conformation even in the presence of a ligand. The destabilizing effects of metal ions may not be negligible as most of them are essential elements in organisms. In contrast, Ba²⁺ was found to be a potent stabilizing cation, which could compete with other destabilizing cations to modulate the stability of the G-quadruplex. Moreover, the destabilizing effects of divalent or trivalent cations were considerably inhibited when a metal chelator was used. These data suggested that the unfavorable effects of destabilizing cations must be minimized for enhancing the ligand-mediated stabilization of the G-quadruplex.