On matching and mismatching in protein chemistry

Post-translational protein editing methods that rely upon precise chemical alteration of sequence and hence function are of increasing utility. Whilst the role of proteins as chiral environments is functionally ubiquitous in their interaction with substrates or ligands, the influence of stereochemical ‘matching/mismatching’ effects upon the reactivity of chemical reagents designed for such editing is essentially unexplored. The reagent dibromohexanediamide (DBHDA) is a useful reagent for the chemical transformation of cysteine to dehydroalanine (Dha) in proteins and peptides. Differences in reactivities of the stereoisomers of DBHDA, if any, in different protein substrates are unknown. Here, we report synthetic access to these isomers and reveal apparent stereochemically ‘matched vs mismatched’ differences in reactivity, that, in principle, in the future might be exploited to expand the methods available for residue- and site-selective editing.