Glutathione radical: Intramolecular H abstraction by the thiyl radical

Ab initio computations (B3LYP/6-31G(D)) were used to predict transition str uctures and energies of activation for intramolecular H atom transfer to a thiyl radical (RS.) from the alpha -C-H bonds of glutathione (1) and from t he model compounds, N-formylcysteinylglycine (2) and N-(2-thioethanyl)-gamm a -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 B 3LYP/6-311+G(3df,2p) level, were used to derive free energies of activation (DeltaG(not equal)) and reaction (DeltaG degrees). For abstraction of the alpha -C-H (Gly) by the thiyl radical in the gas phase, DeltaG(not equal) = 134 kJ mol(-1) if the amide link to Gly is in the more stable (Z)-configur ation, and DeltaG(not equal) = 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 alpha -C-H (Cys), DeltaG(not equal) = 110 kJ mol(-1). The lowest energy pathway for intramolecular H-transfer to the thiyl radic al is from alpha -C-H (Gln), DeltaG(not equal) = 37-42 kJ mol(-1), and corr esponds rather well with experimental results in solution (DeltaG(not equal ) = 43 kJ mol(-1)). The calculated free energy change for the equilibrium b etween thiyl and alpha -C forms of the glutathione radical is DeltaG degree s = -54 kJ mol(-1). The value estimated from experimental data is DeltaG de grees = -37 kJ mol(-1). The agreement between the energies from theory in t he gas phase and experiment in solution suggests that the free energies of solvation of reactant thiyl radical, transition structures for H abstractio n, and the product alpha -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 mod est lowering of the activation free energy. The results from the COSMO meth od were inconclusive as to whether a rate enhancement or decrease could be expected.