Steric Effects on the Chelation of Mn2+ and Zn2+ by Hexadentate Polyimidazole Ligands: Modeling Metal Binding by Calprotectin Site 2

Recently, there has been increasing interest in the design of ligands that bind Mn2+ with high affinity and selectivity, but this remains a difficult challenge. It has been proposed that the cavity size of the binding pocket is a critical factor in most synthetic and biological examples of selective Mn2+ binding. Here, we use a bioinspired approach adapted from the hexahistidine binding site of the manganese-sequestering protein calprotectin to systematically study the effect of cavity size on Mn2+ and Zn2+ binding. We have designed a hexadentate, trisimidazole ligand whose cavity size can be tuned through peripheral modification of the steric bulk of the imidazole substituents. Conformational dynamics and redox potentials of the complexes are dependent on ligand steric bulk. Stability constants are consistent with the hypothesis that larger ligand cavities are relatively favorable for Mn2+ over Zn2+, but this effect alone may not be sufficient to achieve Mn2+ selectivity.