A push–pull mechanism helps design highly competent G-quadruplex-DNA catalysts

Massive efforts are currently being invested to improve the performance, versatility, and scope of applications of nucleic acid catalysts. G-quadruplex (G4)/hemin DNAzymes are of particular interest owing to their structural programmability and chemical robustness. However, optimized catalytic efficiency is still bottleneck and the activation mechanism is unclear. Herein, we have designed a series of parallel G4s with different proximal cytosine (dC) derivatives to fine-tune the hemin-binding pocket for G4-DNAzymes. Combining theoretical and experimental methods, we have assessed the dependence of catalytic enhancement on the electronic properties of proximal dCs and demonstrated how proximal dCs activate catalytic proficiency. These results provide interesting clues in recapitulating the push–pull mechanism as the basis of peroxidase activity and help to devise a new strategy to design highly competent DNA catalysts whose performances are of the same order as protease.