Metallopeptide Based Mimics with Substituted Histidines Approximate a Key Hydrogen Bonding Network in the Metalloenzyme Nickel Superoxide Dismutase

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Abstract
Nickel superoxide dismutase (NiSOD) is a recently discovered superoxide dismutase that utilizes the NiIII/NiII couple to facilitate the disproportionation of O2•− into H2O2 and O2. A key structural component of NiSOD is an elongated axial His-imidazole NiIII 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 ({NiIII/II(SODM1−Im−X)} X = Me, H, DNP, and Tos; SODM1−Im−X = H′CDLPCGVYDPA where H′ is an N-substituted His). All reduced {NiII(SODM1−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 NiIIN2S2 center. In contrast, changes to the axial His(1) ligand impart differential spectroscopic properties on the oxidized {NiIII(SODM1−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 NiIII−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 NiIII contained in a square pyramidal coordination environment, but show changes in the hyperfine coupling to 14N along gz. This is attributable to a reorientation of the gz vector in the more (along the NiIII−Nimidazole bond) versus less (along the S−NiIII−Namine bond) Lewis basic imidazole bases. This reorientation of gz along the xy plane translates into a decrease in Azz 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 kcat 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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