QM/MM modeling of the glutathione–hydroxymethyl radical reaction in water

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Abstract
The reactions of hydroxymethyl radical ˙CH2OH with glutathione tripeptide GSH and with methylthiol CH3SH in water are modeled by using the effective fragment potential (EFP) based quantum mechanical–molecular mechanical (QM/MM) methods. In the case of glutathione, the reactive part of the cysteine residue of the tripeptide and the hydroxymethyl moiety are included to the quantum part. The remaining part of GSH assigned to the MM subsystem is represented by flexible chains of small effective fragments. The energy profiles for the condensed phase reactions have been constructed by using the transition state structure of the gas-phase reference reaction of hydroxymethyl radical ˙CH2OH with methylthiol CH3SH. Optimization of geometry parameters of the systems, including coordinates of environmental particles, leads to the structures at the top of the barrier, as well as for reagent interaction complexes and product interaction complexes. The energy difference between the top of the barrier and the reagent interaction complex is considered as a measure of activation energy, which allows us to treat all systems at the uniform level. According to simulation results, the activation barrier for the aqueous reaction of hydroxymethyl radical with methylthiol should be slightly higher, and for the aqueous reaction of hydroxymethyl radical with glutathione in the lowest energy conformation should be slightly lower than that of the reference gas-phase reaction. A conclusion about higher activation barrier for aqueous reaction ˙CH2OH+CH3SH in comparison to the gas-phase process, obtained here within the supermolecular approach, is consistent with the literature results of solvation models. It is shown that conformations of peptide chain of glutathione may modify the gas-phase reaction energy profile of the reacting species to a larger extent than the influence of water molecules. The role of the peptide chain seems to be to provide either beneficial or unfavorable arrangement of the reagents in the interaction complex.

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