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Density functional theory calculations on the active site of biotin synthase: mechanism of S transfer from the Fe2S2 cluster and the role of 1st and 2nd sphere residues

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Abstract

Density functional theory (DFT) calculations are performed on the active site of biotin synthase (BS) to investigate the sulfur transfer from the Fe2S2 cluster to dethiobiotin (DTB). The active site is modeled to include both the 1st and 2nd sphere residues. Molecular orbital theory considerations and calculation on smaller models indicate that only an S atom (not S2−) transfer from an oxidized Fe2S2 cluster leads to the formation of biotin from the DTB using two adenosyl radicals generated from S-adenosyl-l-methionine. The calculations on larger protein active site model indicate that a 9-monothiobiotin bound reduced cluster should be an intermediate during the S atom insertion from the Fe2S2 cluster consistent with experimental data. The Arg260 bound to Fe1, being a weaker donor than cysteine bound to Fe2, determines the geometry and the electronic structure of this intermediate. The formation of this intermediate containing the C9–S bond is estimated to have a ΔG≠ of 17.1 kcal/mol while its decay by the formation of the 2nd C6–S bond is calculated to have a ΔG≠ of 29.8 kcal/mol, i.e. the 2nd C–S bond formation is calculated to be the rate determining step in the cycle and it leads to the decay of the Fe2S2 cluster. Significant configuration interaction (CI), present in these transition states, helps lower the barrier of these reactions by ~30–25 kcal/mol relative to a hypothetical outer-sphere reaction. The conserved Phe285 residue near the Fe2S2 active site determines the stereo selectivity at the C6 center of this radical coupling reaction.

Graphical Abstract

Reaction mechanism of BS investigated using DFT calculations. Strong CI and the Phe285 residue control the kinetic rate and stereochemistry of the product.

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Acknowledgments

This research is funded by IACS departmental grant and MNRE project (103/108/2010-NT). AR acknowledges the IntPhd program of IACS. SD acknowledges SRF from CSIR, India.

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Authors and Affiliations

  1. Department of Inorganic Chemistry, Indian Association for the Cultivation of Science, Kolkata, 700032, West Bengal, India

    Atanu Rana, Subal Dey, Amita Agrawal & Abhishek Dey

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  1. Atanu Rana
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  2. Subal Dey
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Correspondence to Abhishek Dey.

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775_2015_1296_MOESM1_ESM.pdf

Supplementary material 1 (PDF 77 kb) The optimized coordinates are available free of charge at http://pubs.acs.org

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Rana, A., Dey, S., Agrawal, A. et al. Density functional theory calculations on the active site of biotin synthase: mechanism of S transfer from the Fe2S2 cluster and the role of 1st and 2nd sphere residues. J Biol Inorg Chem 20, 1147–1162 (2015). https://doi.org/10.1007/s00775-015-1296-9

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