Coordination interactions between transition metals ions and biomolecules have long been appreciated to be an essential component of biological function within living organisms, such as in the self-assembly of biological proteins and transport and sequestration of ions and molecules. More recently, there has been a growing appreciation of how these coordination interactions might facilitate load-bearing ability in biogenic materials. For instance, marine mussels are thought to incorporate metal ions into cuticles to produce high hardness and extensibility, properties that are often diametric in synthetic materials. Marine worms also incorporate metal-coordination crosslinks in their hard, condensed mandibular structure. One example of biological metal coordination is the coordination interaction between histidine and common transition metals such as Ni 2+ , Zn 2+ , and Cu 2+ , which has been implicated to facilitate diverse mechanical behavior ranging from hardness in the jaws of the Glycera and Nereis to dissipation in the byssal threads of the Mytilus (Fig. ). Accordingly, there has been growing interest in utilizing the interactions between common biogenic transition metals and histidine (or imidazole, the functional group in histidine) as cross-linkers in synthetic materials, such as in polymer materials and histidine-rich protein-based materials. Despite this growing application of imidazole-M 2+ interactions in synthetic soft materials, there is an unresolved understanding of the molecular origins of the different dissociation rates exhibited by imidazole motifs crosslinked with Ni 2+ , Zn 2+ , and Cu 2+ ions in these materials. A complicating factor in understanding the "hierarchy" of binding between histidine and these transition metals is that the hierarchy appears to be strongly system or configuration dependent. For instance, the relaxation times of polymer networks crosslinked by coordination between histamine (an imidazole group with an additional amine group) and Ni 2+ , Zn 2+ , and Cu 2+ ions follows a hierarchy of Ni 2+ > Cu 2+ > Zn 2+ , and the same order is observed in polymer melts crosslinked by acetate ligands and the same metals. This behavior is contrasted by the mechanical reinforcement of synthetic hydrogels with imidazole-rich protein residues; the modulus of these imidazole-rich protein networks crosslinked with transition metal ions show Zn 2+ > Ni 2+ for polymer networks with imidazole-rich coiled-coil cross-linking motifs, and also for acrylamide copolymer networks with imidazole functional groups. A similar trend of Zn 2+ > Ni 2+ > Cu 2+ is also observed in the case of hydrogels made with imidazole-rich Nvjp-1 protein found in the jaws of the marine sandworm Nereis. A hypothesis to explain the apparent discrepancy in the metal ion hierarchy between histaminecontaining synthetic materials and imidazole-rich protein residues is that both nitrogen atoms in the histamine ligand are available for coordination interactions with M 2+ in synthetic materials, whereas only one nitrogen atom in the imidazole ligand is available coordination interactions in protein systems where the carboxyl and amine groups form the backbone of the protein. However, the cumulative binding stability constants of imidazole and histamine with M 2+ follows a hierarchy of Cu 2+ > Ni 2+ > Zn 2+ , 29 as does DFT calculation results of the interaction between a single imidazole ligand and M 2+ . The Cu 2+ > Ni 2+ > Zn 2+ hierarchy is also predicted by the Irving-Williams series, which ranks the stability of octahedral complexes of amines and thiols with firstrow transition metal ions. These orders are in contrast with the hierarchy presented above for histamine-rich networks and imidazole-rich proteins. In addition, in vitro binding affinities of these transition metals with imidazole-rich Hpn proteins and in vivo selectivity of H. pylori which use Hpn proteins to sequester transition metal ions show different hierarchies of Cu 2+ > Ni 2+ > Zn 2+ and Ni 2+ > Cu 2+ > Zn 2+ , respectively. The exchange time of H2O with these three transition metals, which is yet another measure of the dissociation rates of bound species to the metal ions, follow an order of Ni 2+ > Zn 2+ > Cu 2+ . Thus, the reported binding hierarchies of imidazole-M 2+ interactions are prevalently system-specific (Fig. ).