Computational Insights into the Formation and Structure of S–N Containing Cyclic Peptides

[Image: see text] Cyclic peptides are known to have biologically important roles and may also be applicable to the pharmaceutical and other industries. Furthermore, thiols and amines, which are found throughout biological systems, can react to form S–N bonds and to date, ∼100 biomolecules containing such a bond have been identified. However, while there are in principle numerous S–N containing peptide-derived rings possible, only a few are presently known to occur in biochemical systems. Density functional theory-based calculations have been used to consider the formation and structure of S–N containing cyclic peptides from systematic series of linear peptides in which a cysteinyl has first been oxidized to a sulfenic or sulfonic acid. In addition, the possible effect of the cysteine’s vicinal residue on the free energy of formation has also been considered. In general, when the cysteine is first oxidized to a sulfenic acid, only the formation of smaller S–N containing rings is calculated to be exergonic in aqueous solution. In contrast, when the cysteine is first oxidized to a sulfonic acid, the formation of all rings considered (with one exception) is calculated to be endergonic in aqueous solution. The nature of vicinal residue can influence ring formation through stabilizing or destabilizing intramolecular interactions.