Mechanism and Origin of Chemical Selectivity in Oxaziridine-Based Methionine Modification: A Computational Study

Oxaziridine-based redox sulfur imidation provides a breakthrough strategy for selective modification at methionine in proteins. The chemoselectivity of imidization (N-transfer) over oxidation (O-transfer) of the thioether functionality of methionine, and the modification selectivity of methionine over other amino acids, are the key features of this strategy. To elucidate the detailed reaction mechanism and the origin of the reported chemoselectivity, a theoretical investigation on the oxaziridine-based methionine modification reaction is reported. It is found that both the N-transfer and O-transfer pathways occur in a concerted mechanism. Distortion/interaction activation strain model analysis indicates that the N-transfer chemoselectivity is mainly controlled by the interaction energy. Orbital and charge analysis further supports that the interaction energy resulting from the orbital interaction favors the N-transfer pathway at the early stage of the reaction. The calculated reactivity of eight potential amino acid competitors with the oxaziridine shows excellent selectivity for methionine modification, consistent with the experimental observations. The scarcity of active species in neutral aqueous solution leads to the weak reactivity of tyrosine, lysine, and arginine. The stronger charge-transfer interactions between methionine and the oxaziridine compared with that for the other amino acids also play vital roles in the modification selectivity.