Neutral versus charged species in enzyme catalysis. Classical and free energy barriers for oxygen atom transfer from C4a-hydroperoxyflavin to dimethyl sulfide

Theoretical calculations at the B3LYP/6-31+G(dp) level have been used to study the oxidation of dimethyl sulfide by a series of bicyclic and tricyclic model C4a-flavin hydroperoxides. The intrinsic gas-phase reactivity of tricyclic C4a-hydroperoxyflavin 4 is ca. 10(9) greater than t-BuOOH but is ca. 10(7) less reactive toward the oxidation of dimethyl sulfide than peroxyformic acid. The S(N)2-like attack of the nucleophile on the distal oxygen of the hydroperoxide and the relative reactivity of the peracid are in excellent agreement with the earlier experimental data of Bruice. The effect of N-1 or N-5 hydrogen-bonding interactions on the activation barriers for oxygen atom transfer have been examined. Classical energy barriers for oxygen atom transfer from neutral and ion-paired forms of C4a-hydroperoxyflavin to dimethyl sulfide are predicted to differ by a small margin, suggesting that proton distribution exerts a relatively small influence on the reactivity of alkyl hydroperoxides. Isolated N-1- and N-5-protonated cations exhibit artificially low barriers as a consequence of their location in a high energy region of the potential energy surface domain.