A Water Molecule Triggers Guest Exchange at a Mono-Zinc Centre Confined in a Biomimetic Calixarene Pocket: a Model for Understanding Ligand Stability in Zn Proteins

In this study, the ligand exchange mechanism at a biomimetic Zn^II centre, embedded in a pocket mimicking the possible constrains induced by a proteic structure, is explored. The residence time of different guest ligands (dimethylformamide, acetonitrile and ethanol) inside the cavity of a calix[6]arene-based tris(imidazole) tetrahedral zinc complex was probed using 1D EXchange SpectroscopY NMR experiments. A strong dependence of residence time on water content was observed with no exchange occurring under anhydrous conditions, even in the presence of a large excess of guest ligand. These results advocate for an associative exchange mechanism involving the transient exo-coordination of a water molecule, giving rise to 5-coordinate Zn^II intermediates, and inversion of the pyramid at the Zn^II centre. Theoretical modelling by DFT confirmed that the associative mechanism is at stake. These results are particularly relevant in the context of the understanding of kinetic stability/lability in Zn proteins and highlight the key role that a single water molecule can play in catalysing ligand exchange and controlling the lability of Zn^II in proteins.