Exploring the Effects of H-Bonding in Synthetic Analogues of Nickel Superoxide Dismutase (Ni-SOD): Experimental and Theoretical Implications for Protection of the Ni-SCys Bond

Nickel superoxide dismutase (Ni-SOD) is a recently discovered SOD obtained from soil microbes and cyanobacteria that shares no structural or spectroscopic similarities with other isoforms of SOD. The enzyme is found in both the NiII (Ni-SODred) and NiIII (Ni-SODox) oxidation states in “as isolated” preparations of the enzyme from two separate and independently crystallized Streptomyces strains. Ni-SOD contains an unusual and unprecedented biological coordination sphere comprised of Cys-S and peptido-N donors. To understand the role of these donors, we have previously synthesized the monomeric NiIIN2S2 complexes, (Et4N)[Ni(nmp)(SC6H4-p-Cl)] (2) and (Et4N)[Ni(nmp)(StBu)] (3) as Ni-SODred models arising from the S,S-bridged precursor molecule, [Ni2(nmp)2] (1) (where nmp2- = doubly deprotonated form of N-2-(mercaptoethyl)picolinamide). In addition to 2 and 3, we report here three new complexes, (Et4N)[Ni(nmp)(S-o-babt)] (4), (Et4N)[Ni(nmp)(S-meb)] (5), and K[Ni(nmp)(S-NAc)] (6) (where−S-o-babt = thiolate of o-benzoylaminobenzene thiol; −S-meb = thiolate of N-(2-mercaptoethyl)benzamide; and −S-NAc = thiolate of N-acetyl-l-cysteine methyl ester), that provide a unique comparison as to the structural and reactivity effects imparted by H-bonding in square planar asymmetrically coordinated NiIIN2S2 complexes. X-ray structural analysis in combination with cyclic voltammetry (CV), spectroscopic measurements, density functional theory (DFT) calculations, and reactivity studies with O2 and various ROS were employed to gain insight into the role that H-bonding plays in NiN2S2 complexes related to Ni-SOD. The experimental results coupled with theoretical analysis demonstrate that H-bonding to coordinated thiolates stabilizes S-based molecular orbitals relative to those arising from NiII, allowing for enhanced Ni contribution to the highest occupied molecular orbital (HOMO), which is predominantly of S−Ni π* character. These studies provide a unique perspective on the role played by electronically different thiolates regarding the intimately coupled interplay and delicate balance of Ni- versus S-based reactivity in Ni-SOD model complexes. The reported results have offered new insight into the chemistry that H-bonding/thiolate protonation imparts upon the Ni-SOD active site during catalysis, in particular, as a protective mechanism against oxidative modification/degradation.