Oxygen radical-mediated oxidation reactions of an alanine peptide motif - density functional theory and transition state theory study

Background: Oxygen-base (O-base) oxidation in protein backbone is important in the protein backbone fragmentation due to the attack from reactive oxygen species (ROS). In this study, an alanine peptide was used model system to investigate this O-base oxidation by employing density functional theory (DFT) calculations combining with continuum solvent model. Detailed reaction steps were analyzed along with their reaction rate constants. Results: Most of the O-base oxidation reactions for this alanine peptide are exothermic except for the bond-breakage of the C-alpha-N bond to form hydroperoxy alanine radical. Among the reactions investigated in this study, the activated energy of OH alpha-H abstraction is the lowest one, while the generation of alkylperoxy peptide radical must overcome the highest energy barrier. The aqueous situation facilitates the oxidation reactions to generate hydroxyl alanine peptide derivatives except for the fragmentations of alkoxyl alanine peptide radical. The C-alpha-C-beta bond of the alkoxyl alanine peptide radical is more labile than the peptide bond. Conclusion: the rate-determining step of oxidation in protein backbone is the generation of hydroperoxy peptide radical via the reaction of alkylperoxy peptide radical with HO2. The stabilities of alkylperoxy peptide radical and complex of alkylperoxy peptide radical with HO2 are crucial in this O-base oxidation reaction.