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

Nickel superoxide dismutase (NiSOD) is a recently discovered superoxide dismutase that utilizes the Ni-III/Ni-II couple to facilitate the disproportionation of O-2(center dot-) into H2O2 and O-2. A key structural component of NiSOD is an elongated axial His-imidazole Ni-III bond (2.3-2.6 angstrom) 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) epsilon-nitrogen substituted imidazoles to approximate the electronic influence of this H-bonding network ({Ni-III/II(SODM1-lm-X)} X = Me, H, DNP, and Tos; SODM1-lm-X = H'CDLPCGVYDPA where H' is an N-substituted His). All reduced {Ni-II(SODM1-lm-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 (NiN2S2)-N-II center. In contrast, changes to the axial His(1) ligand impart differential spectroscopic properties on the oxidized {Ni-III(SODM1-lm-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 1.70mdyn angstrom(-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 N-14 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 similar to 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) x 10(6) M-1 s(-1) for the metallopeptide with the most Lewis basic imidazole to 6(2) x 10(8) 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.