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  • Unraveling gold(I)-specific action towards peptidic disulfide cleavage: a DFT investigation.

Unraveling gold(I)-specific action towards peptidic disulfide cleavage: a DFT investigation.

Chemphyschem : a European journal of chemical physics and physical chemistry (2011-11-02)
Elise Dumont, Carine Michel, Philippe Sautet
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 -CH(2)-S-S-CH(2)- 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-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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Dimethyl disulfide, ≥99.0%
Sigma-Aldrich
Dimethyl disulfide, ≥98%, FG