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The active E4 structure of nitrogenase studied with different DFT functionals.

ABSTRACT: The present study concerns the technical aspects of obtaining the energetics for the E4 state of nitrogenase, the enzyme that fixes N₂ in nature. EPR experiments have shown that the critical E4 structure that activates N₂ should contain two bridging hydrides in the FeMo-cofactor. It is furthermore in equilibrium with a structure where the two hydrides have been released and N₂ binds. These observations led to the suggestion that E4 should have two bridging hydrides and two protonated sulfides. It is important to note that the structure for E4 has not been determined, but only suggested. For a long time, no DFT study led to the suggested structure, independent of which functional was used. However, in two recent DFT studies a good agreement with the experimental suggestion was claimed to have been obtained. In one of them the TPSS functional was used. That was the first out of 11 functionals tried that led to the experimentally suggested structure. In the second of the recent DFT studies, a similar conclusion was reached using the TPSSh functional. The conclusions in the recent studies have here been studied in detail, by calculating a critical energetic value strongly implied by the same EPR experiments. Both the TPSS and TPSSh functionals have been used. The present calculations suggest that those DFT functionals would not lead to agreement with the experimental EPR results either.

SUBMITTER: Wei WJ

PROVIDER: S-EPMC7756797 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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The active E4 structure of nitrogenase studied with different DFT functionals.

Wei Wen-Jie WJ Siegbahn Per E M PEM

Journal of computational chemistry 20201014 2

The present study concerns the technical aspects of obtaining the energetics for the E4 state of nitrogenase, the enzyme that fixes N2 in nature. EPR experiments have shown that the critical E4 structure that activates N2 should contain two bridging hydrides in the FeMo-cofactor. It is furthermore in equilibrium with a structure where the two hydrides have been released and N2 binds. These observations led to the suggestion that E4 should have two bridging hydrid ...[more]

PMID: 33051882

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Project description:Molybdenum nitrogenase is one of the most intriguing metalloenzymes in nature, featuring an exotic iron-molybdenum-sulfur cofactor, FeMoco, whose mode of action remains elusive. In particular, the molecular and electronic structure of the N2-binding E4 state is not known. In this study we present theoretical QM/MM calculations of new structural models of the E4 state of molybdenum-dependent nitrogenase and compare to previously suggested models for this enigmatic redox state. We propose two models as possible candidates for the E4 state. Both models feature two hydrides on the FeMo cofactor, bridging atoms Fe2 and Fe6 with a terminal sulfhydryl group on either Fe2 or Fe6 (derived from the S2B bridge) and the change in coordination results in local lower-spin electronic structure at Fe2 and Fe6. These structures appear consistent with the bridging hydride proposal put forward from ENDOR studies and are calculated to be lower in energy than other proposed models for E4 at the TPSSh-QM/MM level of theory. We critically analyze the DFT method dependency in calculations of FeMoco that has resulted in strikingly different proposals for this state. Importantly, dinitrogen binds exothermically to either Fe2 or Fe6 in our models, contrary to others, an effect rationalized via the unique ligand field (from the hydrides) at the Fe with an empty coordination site. A low-spin Fe site is proposed as being important to N2 binding. Furthermore, the geometries of these states suggest a feasible reductive elimination step that could follow, as experiments indicate. Via this step, two electrons are released, reducing the cofactor to yield a distorted 4-coordinate Fe2 or Fe6 that partially activates N2. We speculate that stabilization of an N2-bound Fe(i) at Fe6 (not found for Fe2 model) via reductive elimination is a crucial part of N2 activation in nitrogenases, possibly aided by the apical heterometal ion (Mo or V). By using protons from the sulfhydryl group (to regenerate the sulfide bridge between Fe2 and Fe6) and the nearby homocitrate hydroxy group, we calculate a plausible route to yield a diazene intermediate. This is found to be more favorable with the Fe6-bound model than the Fe2-bound model; however, this protonation is uphill in energy, suggesting protonation of N2 might occur later in the catalytic cycle or via another mechanism.

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The active E4 structure of nitrogenase studied with different DFT functionals.

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The active E4 structure of nitrogenase studied with different DFT functionals.

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