| Sumario: | Broken-symmetry density functional theory (BS-DFT) has been used to address the redox-dependent structural changes of the proximal [4Fe-3S] cluster, implicated in the O-tolerance of membrane-bound [NiFe]-hydrogenase (MBH). The recently determined structures of the [4Fe-3S] cluster together with its protein ligands were studied at the reduced [4Fe-3S], oxidized [4Fe-3S], and superoxidized [4Fe-3S] levels in context of their relative energies and protonation states. The observed proximal cluster conformational switch, concomitant with the proton transfer from the cysteine Cys20 backbone amide to the nearby glutamate Glu76 carboxylate, is found to be a single-step process requiring ~12–17 kcal/mol activation energy at the superoxidized [4Fe-3S] level. At the more reduced [4Fe-3S] oxidation levels, this rearrangement has at least 5 kcal/mol higher activation barriers and prohibitively unfavorable product energies. The reverse transformation of the proximal cluster is a fast unidirectional process with ~8 kcal/mol activation energy, triggered by one-electron reduction of the superoxidized species. A previously discussed ambiguity of the Glu76 carboxylate and 'special' Fe4 iron positions in the superoxidized cluster is now rationalized as a superposition of two local minima, where Glu76-Fe4 coordination is either present or absent. The calculated 12.3–17.9 MHz N hyperfine coupling (HFC) for the Fe4-bound Cys20 backbone nitrogen is in good agreement with the large 13.0/14.6 MHz N couplings from the latest HYSCORE/ENDOR studies.
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