Nickel superoxide dismutase (NiSOD) is a recently discovered superoxide dismutase that utilizes the Ni^III/Ni^II couple to facilitate the disproportionation of O₂^•− into H₂O₂ and O₂. A key structural component of NiSOD is an elongated axial His-imidazole Ni^III bond (2.3−2.6 Å) that is the result of a H-bonding network between His(1), Glu(17), and Arg(47). Herein we utilize metallopeptide based mimics of NiSOD with His(1) ε-nitrogen substituted imidazoles to approximate the electronic influence of this H-bonding network ({Ni^III/II(SOD^M1−Im−X)} X = Me, H, DNP, and Tos; SOD^M1−Im−X = H′CDLPCGVYDPA where H′ is an N-substituted His). All reduced {Ni^II(SOD^M1−Im−X)} are similar to one another as assessed by electronic absorption spectroscopy, circular dichroism (CD) spectroscopy, and Ni K-edge x-ray absorption (XAS). This indicates that the change in His(1) is having little influence on the square-planar Ni^IIN₂S₂ center. In contrast, changes to the axial His(1) ligand impart differential spectroscopic properties on the oxidized {Ni^III(SOD^M1−Im−X)} metallopeptides. Resonance Raman spectroscopy (405 nm excitation) in conjunction with a normal coordinate analysis indicates that as the axial His imidazole is made less Lewis basic there is an increase in Ni^III−S bond strength in the equatorial plane, with force constants for the Ni−S bond trans to the amine ranging from 1.54 to 1.70 mdyn Å⁻¹. The rhombic electron paramagnetic resonance (EPR) spectra of the four oxidized metallopeptides are all consistent with low-spin Ni^III contained in a square pyramidal coordination environment, but show changes in the hyperfine coupling to ¹⁴N along g_z. This is attributable to a reorientation of the g_z vector in the more (along the Ni^III−N^imidazole bond) versus less (along the S−Ni^III−N^amine bond) Lewis basic imidazole bases. This reorientation of g_z along the xy plane translates into a decrease in A_zz by ∼20 MHz. A decrease in Lewis-basicity of the axial imidazole also translates into a 2 orders of magnitude increase in SOD catalysis across the metallopeptide series, with k_cat ranging from 6(1) × 10⁶ M⁻¹ s⁻¹ for the metallopeptide with the most Lewis basic imidazole to 6(2) × 10⁸ M⁻¹ s⁻¹ for the metallopeptide with the least basic imidazole. This likely results from a fine-tuning of the electron transfer properties of the Ni-center, which optimize it for SOD catalysis.

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