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Does the environment around the H-cluster allow coordination of the pendant amine to the catalytic iron center in [FeFe] hydrogenases? Answers from theory

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Abstract

[FeFe] hydrogenases are H2-evolving enzymes that feature a diiron cluster in their active site (the [2Fe]H cluster). One of the iron atoms has a vacant coordination site that directly interacts with H2, thus favoring its splitting in cooperation with the secondary amine group of a neighboring, flexible azadithiolate ligand. The vacant site is also the primary target of the inhibitor O2. The [2Fe]H cluster can span various redox states. The active-ready form (Hox) attains the FeIIFeI state. States more oxidized than Hox were shown to be inactive and/or resistant to O2. In this work, we used density functional theory to evaluate whether azadithiolate-to-iron coordination is involved in oxidative inhibition and protection against O2, a hypothesis supported by recent results on biomimetic compounds. Our study shows that Fe–N(azadithiolate) bond formation is favored for an FeIIFeII active-site model which disregards explicit treatment of the surrounding protein matrix, in line with the case of the corresponding FeIIFeII synthetic system. However, the study of density functional theory models with explicit inclusion of the amino acid environment around the [2Fe]H cluster indicates that the protein matrix prevents the formation of such a bond. Our results suggest that mechanisms other than the binding of the azadithiolate nitrogen protect the active site from oxygen in the so-called H inactox state.

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Scheme 1
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Scheme 3

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Notes

  1. Phosphorous-bound methyl and phenyl groups were disregarded in such an analysis, given the flatness of the energy landscape associated with their rotation.

  2. In the electronic supplementary material, we also present results for alternative medium-sized models that include either the side chain of Cys178 (a residue that is capable of establishing a hydrogen bond with the amine group of the pendant as shown in Scheme 1; model denomination cys M, Fig. S3) or a fragment of the protein backbone surrounding Ala109 (a residue that is hydrogen-bonded to the Fep-bound CN– group; model termed ala M, Fig. S4). In both the cys M model and the ala M model, the Hoverox state featuring an Fed–N bond is stabler than the alternative conformation in which such a bond is absent. In the Hox state of both cys M and ala M, the Fed–N bond can form, but the resulting conformations are 2.7 and 4.1 kcal mol–1 less stable than the alternative isomers without such a bond (see the electronic supplementary material for further details).

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Acknowledgments

Financial support of this work from the Cluster of Excellence “Unifying Concepts in Catalysis” (Berlin) is gratefully acknowledged; We acknowledge the CINECA award under the ISCRA initiative, for the availability of high performance computing resources and support. C.L., F.V., and C.B. acknowledge the CNRS, Aix-Marseille Université, and the ANR (ANR-12-BS08-0014) for funding.

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Authors and Affiliations

  1. Begegnungszentren der IGAFA, IBZ Berlin-Adlershof, Wilhelm-Ostwald-Str. 3, 12489, Berlin, Germany

    Toshiko Miyake

  2. Department of Environmental and Earth Sciences, Università degli Studi di Milano Bicocca, Piazza della Scienza 1, 20126, Milan, Italy

    Maurizio Bruschi, Ugo Cosentino & Claudio Greco

  3. BIP UMR 7281, IMM FR 3479, CNRS, Aix-Marseille Université, 31 Chemin Joseph Aiguier, 13402, Marseille Cedex 20, France

    Carole Baffert, Vincent Fourmond & Christophe Léger

  4. Department of Biotechnology and Biosciences, Università degli Studi di Milano Bicocca, Piazza della Scienza 2, 20126, Milan, Italy

    Giorgio Moro & Luca De Gioia

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  1. Toshiko Miyake
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Correspondence to Luca De Gioia or Claudio Greco.

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Miyake, T., Bruschi, M., Cosentino, U. et al. Does the environment around the H-cluster allow coordination of the pendant amine to the catalytic iron center in [FeFe] hydrogenases? Answers from theory. J Biol Inorg Chem 18, 693–700 (2013). https://doi.org/10.1007/s00775-013-1014-4

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