Challenges persist in replicating enzyme-like active sites with functional group arrangements in supramolecular catalysis. In this study, we present a supramolecular material comprising Fmoc-modified histidine and copper. We also investigated the impact of noncanonical amino acids (δmH and εmH), isomers of histidine, on the catalytic process. The Fmoc-δmH-based nanoassembly exhibits an approximately 15-fold increase in oxidative activity and an ∼50-fold increase in hydrolytic activity compared to Fmoc-εmH (kcat/Km). This distinction arises from differences in basicity and ligation properties between the ε- and δ-nitrogen of histidine. The addition of guanosine monophosphate further enhances the oxidative activity of the histidine- and methylated histidine-based catalysts. The Fmoc-δmH/Cu2+-based nanoassembly catalyzes the oxidation/hydrolysis cascade of 2',7'-dichlorofluorescein diacetate, benefiting from the synergistic effect between the copper center and the nonligating ε-nitrogen of histidine. These findings advance the biomimetic catalyst design and provide insights into the mechanistic role of essential residues in natural systems.
Keywords: biocatalysis; enzyme mimic; histidine; self-assembly; tautomeric preference.