Metal-triggered topology switching in bipyridine-modified DNA G-quadruplexes

Gaining control over DNA G-quadruplex topology bears potential to modulate and study their interaction with other biomacromolecules such as proteins. To achieve this, we introduced bipyridine ligands into short oligonucleotide strands derived from telomeric regions of humans and Tetrahymena as well as into an oncogenic promoter region capable of forming such G-quadruplexes. This modification makes it possible to dynamically access different G-quadruplex topologies through the formation of chelate complexes within the quadruplex loop regions using metals such as Cu2+, Ni2+, Zn2+, Co2+, and Cd2+. The metal-coordinated systems show enhanced stability towards thermal denaturation as well as a solvation-related response in the presence of molecular crowding reagents. Interestingly, these G-quadruplexes modified with bipyridine-metal complexes stay folded in cellulo and therefore show potential for creating new oligonucleotide-based diagnostic agents and therapeutics. Metal-stabilized G-quadruplexes could therefore be suitable as probes to explore protein-G4 interactions, as inducers for G4-dependent cellular processes, or decoys to sequester transcription factors.