Switching G-quadruplex to parallel duplex by molecular rotor clustering

Abstract

Switching of G-quadruplex (G4) structures between variant types of folding has been proved to be a versatile tool for regulation of genomic expression and development of nucleic acid-based constructs. Various specific ligands have been developed to target G4s in K+ solution with therapeutic prospects. Although G4 structures have been reported to be converted by sequence modification or a unimolecular ligand binding event in K+-deficient conditions, switching G4s towards non-G4 folding continues to be a great challenge due to the stability of G4 in physiological K+ conditions. Herein, we first observed the G4 switching towards parallel-stranded duplex (psDNA) by multimolecular ligand binding (namely ligand clustering) to overcome the switching barrier in K+. Purine-rich sequences (e.g. those from the KRAS promoter region) can be converted from G4 structures to dimeric psDNAs using molecular rotors (e.g. thioflavin T and thiazole orange) as initiators. The formed psDNAs provided multiple binding sites for molecular rotor clustering to favor subsequent structures with stability higher than the corresponding G4 folding. Our finding provides a clue to designing ligands with the competency of molecular rotor clustering to implement an efficient G4 switching.

Topological effect of an intramolecular split G-quadruplex on thioflavin T binding and fluorescence light-up

“…Thioavin T (ThT) as a cationic benzothiazole dye possesses stable uorescence properties, cell penetration capability and low toxicity, and was rst utilized as a uorescent probe for monitoring amyloid in tissue sections. 26 In the last decade, ThT whose weak uorescence at 492 nm also can be intensied upon binding to specic nucleic acids, [27][28][29] has been applied for detecting potassium ions, imaging intracellular nucleic acids and monitoring RNA metabolism in vivo. [29][30][31] For example, ThT triggered G4 folding in the 22AG human telomeric DNA, producing 2100-fold enhanced uorescence, and exhibited high selectivity toward distinct G4 structures.…”

Insect multimeric G-quadruplexes fold into antiparallel structures of different compactness and stability in K+ and Na+ solutions

“…[1][2][3] Hoogsteen hydrogen bonds can stabilize the G-quadruplex structures in the presence of metal cations. [4][5][6][7] G-quadruplexes-forming oligonucleotides always exist in the eukaryotic telomeres and the promoter gene regions. 7,8 The formation of the G-quadruplex signicantly impacts several biological events.…”