Unraveling Gold(I)-Specific Action Towards Peptidic Disulfide Cleavage: A DFT Investigation

Authors

  • Dr. Elise Dumont,

    Corresponding author
    1. Laboratoire de Chimie, UMR 5182 CNRS, Institut de Chimie de Lyon, CNRS, Université de Lyon, École normale supérieure de Lyon, 15 parvis René Descartes, 69364 Lyon Cedex 07 (France)
    • Laboratoire de Chimie, UMR 5182 CNRS, Institut de Chimie de Lyon, CNRS, Université de Lyon, École normale supérieure de Lyon, 15 parvis René Descartes, 69364 Lyon Cedex 07 (France)
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  • Dr. Carine Michel,

    1. Laboratoire de Chimie, UMR 5182 CNRS, Institut de Chimie de Lyon, CNRS, Université de Lyon, École normale supérieure de Lyon, 15 parvis René Descartes, 69364 Lyon Cedex 07 (France)
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  • Dr. Philippe Sautet

    1. Laboratoire de Chimie, UMR 5182 CNRS, Institut de Chimie de Lyon, CNRS, Université de Lyon, École normale supérieure de Lyon, 15 parvis René Descartes, 69364 Lyon Cedex 07 (France)
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Abstract

Ground-state disulfide dissociation is a target of prime importance in structural biochemistry. A main difficulty consists in avoiding competition with carbon–sulfur and backbone scission pathways. In tandem mass spectrometry, such selectivity is afforded using transition elements or coinage-metal ions as catalyst. Yet, the underlying gas-phase mechanistic details remain poorly understood. Gold(I)-assisted disulfide cleavage is investigated by means of DFT calculations, to elucidate the highly selective and specific catalytic action of this transition-metal cation, a most promising one in tandem mass spectrometry. The preferential cleavage of sulfur–sulfur versus carbon–sulfur linkages on dimethyldisulfide, taken as a prototypical aliphatic compound, is rationalized on the basis of molecular orbital arguments. Secondly, it is revealed that the disulfide dissociation profile is dramatically impacted by a peptidic environment. Calculations on l,l-cystine derivatives show two main factors: the topological frustration for an embedded -CH2[BOND]S[BOND]S[BOND]CH2- motif induces a 5 kcal mol−1 penalty, whereas electrophilic assistance via complexation of nitrogen and oxygen atoms lowers activation barriers by a factor of 3. S[BOND]S weakening is both thermodynamically and kinetically driven by the versatile coordination mode of gold(I). The influence of amine-terminus group protonation is finally sketched: it gives rise to an intermediate reactivity. This study sheds lights on the key action of the peptidic environment in tuning the dissociation profile in the presence of this transition-metal monocation.

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