Coordination chemistry inspired by nickel superoxide dismutase
Gale, Eric Michael
MetadataShow full item record
Nickel superoxide dismutase (Ni-SOD) catalyzes the disproportionation of the cytotoxic superoxide radical (O2•–) to O2 and H2O2 via toggling between the Ni(II) and Ni(III) oxidation states. The Ni ion is found within a highly unusual coordination sphere. In the reduced (Ni(II)) resting state, the Ni coordination motif entails a primary amine from His1, an anionic carboxamido-N from Cys2 and two thiolato-S arising from Cys2 and Cys6 in a square-planar geometry. In the oxidized (Ni(III)) resting state, the geometry is square-pyramidal, with the imidazole-N from His1 occupying the apical position. In an effort to elucidate the molecular features imparting SOD activity to this unusual assembly, we have undertaken a synthetic modeling approach and prepared a library of targeted Ni-complexes accurately modeling aspects of the Ni-SOD active site. Employing synthetic protocols developed in our laboratory, we pursued a modular strategy allowing for modifications to specific ligand components while leaving other parameters unperturbed. Thus, we have been able to observe the structural, electronic and reactivity effects imparted by fine tuning electronic contributions of singular components and effectively deduce the roles played by individual molecular parameters. Focusing first on the ligand component modeling the Ni-SCys6 bond, we introduced secondary sphere peptides capable of engaging in NH•••S hydrogen-bonding. Such S-directed hydrogen-bonding interactions were found to provide six-fold kinetic protection against S-oxygenation in the presence of large excesses of reactive oxygen species (ROS) such as H2O2. Computational analysis revealed that NH•••S hydrogen-bonding effectively stabilizes the S(π) orbitals relative to the Ni(dπ) orbitals, thus alleviating a strongly destabilizing anti-bonding interaction and promoting reactivity at the Ni ion. Indeed, inspection of the Ni-SOD crystal structure reveals several S-directed hydrogen-bonding interactions and our results provide experimental validation for hydrogen-bonding as a possible mode of cysteinate protection during catalytic turnover under harshly oxidizing conditions. We also found that solvent interactions with coordinated thiolate ligands can greatly influence the behavior of our model complexes in solution. Complexes featuring mono-dentate thiolate ligands modeling Cys6 remain as monomeric species in polar aprotic solvent, but the mono-dentate thiolate becomes labile upon dissolution in water and S,S’-bridged oligomeric species predominate. The magnitude with which this interaction is observed can be loosely correlated to the basicity of the thiolate ligands and highlights a stabilizing role for the surrounding protein, enforcing the NiN2S2 coordination motif. We also used model complexes to probe the role played by the axial imidazole-N ligand. Our studies reveal that an appended N-donor modeling the imidazole side chain serves to transiently stabilize Ni(III) and promotes controlled rearrangement to a single disulfide linked, dinuclear Ni(II) species, which can be quantitatively reduced back to the monomeric model complex; thus approximating some aspects of the Ni(II)/Ni(III) conversion observed in the enzymatic species. An analogous model lacking this crucial axial N-donor was found to be incapable of supporting Ni(III), even transiently, and underwent demetalation/polymerization immediately upon oxidation. This result highlights this labile N-donor as a crucial interaction towards stabilizing Ni(III) during SOD catalysis.