Polarity inversion sensitized G-quadruplex metal sensors with K⁺ tolerance

Due to the high abundance of K⁺ in environments and K⁺-induced high stability of G-quadruplex (G4), developing a selective G4-based fluorescent sensor for other metal ions with K⁺ tolerance is a great challenge. Herein, we found that even in the presence of 15000-fold excess of K⁺, Ba²⁺ exhibits a highly specific binding with a human telomeric G4 (htG4) in comparison with other G4-binding metal ions such as Pb²⁺ and Sr²⁺. This specific binding event can be recognized by a natural fluorophore of hypericin with a lighting-up fluorescence response. Interestingly, inverting the polarity of the most 3' G in htG4 can sensitize the Ba²⁺ response with the retaining Ba²⁺ specificity and K⁺ tolerance. This polarity inversion of htG4 causes a G4 conformation change in K⁺ and the polarity-inverted htG4 tends to favorably dimerize in response to the Ba²⁺ specific binding. To our knowledge, this is the first report that polarity inversion of G4 can be applied to construct a selective metal sensor with K⁺ tolerance. Our findings will open a new way to conveniently regulate the G4 conformation and stability by polarity inversion towards developing high-performance sensors.