Glutathione radical: Intramolecular H abstraction by the thiyl radical

Ab initio computations (B3LYP/6-31G(D)) were used to predict transition structures and energies of activation for intramolecular H atom transfer to a thiyl radical (RS . ) from the α-C—H bonds of glutathione (1) and from the model compounds, N-formylcysteinylglycine (2) and N-(2-thioethanyl)-γ-glutamine (3). For each compound, transition structures were located by in vacuo calculations on the neutral non-zwitterionic system. Thermodynamic functions derived at the same level and single point calculations at the B3LYP/6-311+G(3df,2p) level, were used to derive free energies of activation (ΔG[Formula: see text]) and reaction (ΔG°). For abstraction of the α-C—H (Gly) by the thiyl radical in the gas phase, ΔG[Formula: see text] = 134 kJ mol –1 if the amide link to Gly is in the more stable (Z)-configuration, and ΔG[Formula: see text] = 52 kJ mol –1 if it is in the less stable (E)-configuration. The isomerization of the amide group requires about 95 kJ mol –1 . Previous studies had indicated that for intramolecular reaction of the thiyl radical at α-C—H (Cys), ΔG[Formula: see text] = 110 kJ mol –1 . The lowest energy pathway for intramolecular H-transfer to the thiyl radical is from α-C—H (Gln), ΔG[Formula: see text] = 37–42 kJ mol –1 , and corresponds rather well with experimental results in solution (ΔG[Formula: see text] = 43 kJ mol –1 ). The calculated free energy change for the equilibrium between thiyl and α-C forms of the glutathione radical is ΔG° = –54 kJ mol –1 . The value estimated from experimental data is ΔG° = –37 kJ mol –1 . The agreement between the energies from theory in the gas phase and experiment in solution suggests that the free energies of solvation of reactant thiyl radical, transition structures for H abstraction, and the product α-C-centred radical, are very similar. The effects of solution were estimated by two continuum models (SCIPCM and COSMO). The SCIPCM model yields results very similar to the gas phase, predicting a modest lowering of the activation free energy. The results from the COSMO method were inconclusive as to whether a rate enhancement or decrease could be expected.Key words: glutathione, thiyl radical, α-C-radical, hydrogen transfer.

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