title: Unraveling gold(I)-specific action towards peptidic disulfide cleavage: a DFT investigation.
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.
authors: Laboratoire de Chimie, UMR CNRS, Institut de Chimie de Lyon, Universit de Lyon, Ecole normale suprieure de Lyon, France. Elise.Dumont@ens-lyon.fr
authors: Elise
authors: E
authors: Dumont
authors: Carine
authors: C
authors: Michel
authors: Philippe
authors: P
authors: Sautet
mesh_terms: D003500:Cyclization; D003553:Cystine / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry*; D006046:Gold / Q000737:chemistry*; D007700:Kinetics; D010455:Peptides / Q000737:chemistry*; D053719:Tandem Mass Spectrometry; D013816:Thermodynamics
chemical_list: D004220:Disulfides; D010455:Peptides; C021181:dimethyl disulfide; D003553:Cystine; D006046:Gold