Going beyond the classic His-Asp dyad: H₂O₂-induced carbon protonation unlocks explosive catalytic activity.

Abstract The key conclusion of the work is to rethink the role of the His-Asp. catalytic pair, we have shown that in the presence of H₂O₂/Cu²⁺, it functions as a single supramolecular ensemble, where protonation can affect the carbon skeleton of histidine, which is impossible for an isolated residue. This effect of proximity and systemic destabilization explains the unprecedented catalytic activity of synzymes and paves the way for the creation of selective agents that are activated only in foci with a high concentration of reactive oxygen species.