Metal Ion-Directed G-Quadruplexes: Supramolecular Polymers with Unusual Phase Transitions

Abstract

Supramolecular polymers (SPs) are non-covalent analogues of conventional polymers, constructed from small molecular building blocks connected through directional and reversible interactions.1 These individually weak but collectively cooperative interactions generate one-dimensional assemblies with dynamic, adaptive, and stimuli-responsive properties. In this talk, I will present our recent work on metal ion-directed G-quadruplex supramolecular polymers in water and their unusual thermoresponsive behavior and phase transitions. 2-4 We have discovered, for the first time, that Cu⁺ ions direct guanosine (G) to assemble into an exceptionally stable G-quadruplex that is structurally and functionally distinct from the well-known K⁺-stabilized G-quadruplex found in nucleic acids.2 The resulting G4·Cu⁺ units further self-assemble in water through a combination of π–π stacking, metallophilic interactions, and hydrophobic effects to produce highly robust supramolecular polymers. Remarkably, these aqueous SPs exhibit heating-induced phase transitions. Below the cloud point temperature, dehydration-driven interpolymer crosslinking converts the solution into a hydrogel, whereas above the cloud point, hydrophobic collapse results in macroscopic phase separation, resembling lower critical solution temperature (LCST)-type behavior. Interestingly, the G4·Cu⁺ supramolecular polymers and hydrogels remain stable over both low- and high-temperature regimes, suggesting an overlap between LCST- and upper critical solution temperature (UCST)-type transitions. By introducing suitable water-miscible cosolvents as regulator, we demonstrate that the enthalpic and entropic contributions governing these transitions can be independently tuned (unpublished). The cosolvent shifts the UCST and LCST boundaries in opposite directions, creating an intermediate temperature window where the supramolecular polymer dissociates into a monomeric sol. Consequently, in water–cosolvent mixtures, the system undergoes a gel–sol–gel transition upon monotonic heating. This represents an unusual reentrant supramolecular polymerization driven by sequential UCST- and LCST-like transitions. Beyond Cu⁺, I will also discuss our recent discovery that dimercury(I) ions direct the formation of a highly stable octameric G-quadruplex.3 These assemblies undergo J-type stacking to produce supramolecular polymers and hydrogels with significantly enhanced resistance to aging, dilution, and thermal dissociation compared with conventional K⁺-stabilized G-quadruplex gels. These studies establish metal ion-directed G-quadruplex supramolecular polymers as a versatile platform for engineering programmable phase transitions in water, opening new opportunities for the design of smart soft materials, adaptive supramolecular systems, and reconfigurable biomaterials.