Write-Read-Erase: Macrocyclic Effectors Regulate Imine Expression in Water

Enzymatic molecular recognition and post-modification of specific amino acid residues on target proteins allows for writing, reading and erasing processes that regulate a wide range of biological processes. Herein, we investigate model dynamic chemical systems based on reversible imine formation reactions that adapt their expression in response to macrocyclic effectors. The writing action relies on the formation of the host:guest supramolecular adduct between the macrocycles and the components/constituents. The dynamic condensation reaction reads each action and changes the expression of the imines accordingly, giving a specific constitutional pattern. The strength of the up-regulating or down-regulating effect can be tuned depending on the supramolecular match between the guests and the microenvironments provided by the different macrocycles. Addition of an external scavenger that is a better fit for the host erases the action and reestablishes the initial equilibrium state, regulating the whole process. Control over the selection of the preferred nucleophile or electrophile is achieved in dynamic covalent libraries, a feature of particular interest in the field of protein modification. Furthermore, complex behaviors like constituent selection, (non-)selective amplification/inhibition, and sorting-to-scrambling transitions emerge from the orthogonal action of different macrocycles on the libraries. These results not only represent a remarkable step in increasing the applicability of dynamic imine chemistry in water but also contribute to the development of chemical systems of higher complexity that mimic biological mode-of-actions found in biology.