Small molecule regulated dynamic structural changes of human G-quadruplexes

Abstract

The changes in structure and dynamics of oncogenic (<i>c-MYC</i>) and telomeric (<i>h-TELO</i>) G-rich DNA sequences due to the binding of a novel carbazole derivative (<b>BTC</b>) are elucidated using single-molecule Förster resonance energy transfer (sm-FRET), fluorescence correlation spectroscopy (FCS) and NMR spectroscopy. In contrast to the previous reports on the binding of ligands to pre-folded G-quadruplexes, this work illustrates how ligand binding changes the conformational equilibria of both unstructured G-rich DNA sequences and K⁺-folded G-quadruplexes. The results demonstrate that K⁺ free <i>c-MYC</i> and <i>h-TELO</i> exist as unfolded and partially folded conformations. The binding of <b>BTC</b> shifts the equilibria of both investigated DNA sequences towards the folded G-quadruplex structure, increases the diffusion coefficients and induces faster end-to-end contact formation. <b>BTC</b> recognizes a minor conformation of the <i>c-MYC</i> quadruplex and the two-tetrad basket conformations of the <i>h-TELO</i> quadruplex.