Dalton Trans. 2026 Sep 17. doi: 10.1039/d6dt01884j. Online ahead of print.

ABSTRACT

The metalloenzymes manganese superoxide dismutase (MnSOD) and manganese lipoxygenase (MnLOX) both use a Mn^III-hydroxo/Mn^II-aqua redox couple to mediate concerted proton-electron transfer (CPET) reactions with their biological substrates. Structural studies of these enzymes indicate hydrogen-bonding with the hydroxo/aqua ligands that presumably modulates the CPET reactivity. We previously reported dramatic rate enhancements when a hydrogen-bond acceptor is positioned adjacent to the hydroxo ligand of a Mn^III-hydroxo complex (Opalade et al., J. Am. Chem. Soc., 2021, 143(37), 15159-15175). More modest rate enhancements were observed for the corresponding Mn^III-methoxy complex. In this present study, we use electronic structure computations to investigate the role of hydrogen bonding in modulating the reaction driving force and barrier for CPET reactions of Mn^III-hydroxo and Mn^III-methoxy complexes. DFT computations reveal a significant decrease in activation energy for a Mn^III-hydroxo complex where the hydroxo ligand donates a hydrogen bond to an adjacent Lewis base. This result correlates with observed kinetic rate constants. In contrast, DFT calculations for the Mn^III-methoxy analogue showed that the presence of an adjacent hydrogen-bond acceptor affects the reaction driving force but not the transition-state energy. An analysis of intrinsic bond orbitals (IBOs) allowed us to link the electronic structure changes for CPET reactions of Mn^III-hydroxo and Mn^III-methoxy complexes to arrow-pushing diagrams, highlighting key differences compared to Fe^III-hydroxo complexes. These computational insights emphasize the importance of hydrogen bonding in enhancing CPET reactivity, offering valuable guidance for the design of bioinspired oxidation catalysts.

PMID:42751769 | DOI:10.1039/d6dt01884j