A computational analysis of the interaction between flavin and thiol(ate) groups. Implications for flavoenzyme catalysis

A computational analysis of the interaction between flavin and thiol(ate) groups has been performed using three density functional theory methods (B3LYP, MPW1PW91, and MPWB1K). Oxidized flavin forms a charge-transfer complex with the thiolate anion prior to the generation of a covalent-adduct at the C4a position of the isoalloxazine ring. The computed reactions require a concerted proton transfer to the N5 position of the flavin and show relatively small barriers (<13 kcal/mol). Using different model systems, it was demonstrated that this proton can be delivered to the flavin via a protonated cysteine, or from the carboxyl moiety of glutamic and aspartic acids by utilizing a series of intervening water molecules.