A computational bird's eye view of redox reactivity in the formation of cysteine-lysine covalent linkages

Recently, a new naturally occurring covalent linkage in peptides was characterised, involving a cysteine and a lysine, bridged through a single oxygen atom. The latter was dubbed as the NOS bond, reflecting the individual atoms directly involved in this rather uncommon bond which finds little parallel in lab chemistry. It is found to form under oxidising conditions and reversible upon addition of reducing agents. Further studies have shown that this bond is found over a large variety of systems and organisms, potentially playing an important role in regulation, cellular defense and replication. Not only that, double NOS bonds have been identified and even found to be competitive in relation to the formation of disulfide bonds. This raises several questions about how this exotic bond comes to be, what are the intermediates involved in its formation and how it competes with other pathways of sulfide oxidation (e.g., sulfinic acid formation, disulfide linkage). With this objective in mind, we revisited our first proposed mechanism for the reaction with model electronic structure calculations, adding information about the reactivity with alternative reactive oxygen species (ROS) and other potential competing products of oxidation. We present a reaction network with more than 30 intermediates which provides one of the most encompassing pictures for cysteine oxidation pathways to date.