Insights into the mechanism of methionine oxidation catalyzed by metal (Cu ²⁺, Zn ²⁺, and Fe ³⁺) - Amyloid beta (Aβ) peptide complexes: A computational study

In this DFT study, a mechanism of the oxidation of methionine (Met) amino acid residue catalyzed by the metal (Cu ²⁺, Zn ²⁺, and Fe ³⁺) bound amyloid beta (Aβ) peptide has been proposed. Based on experimental information, two different mechanisms: (1) stepwise and (2) concerted mechanisms for this important process have been investigated. The B3LYP calculations suggest that in the stepwise mechanism, the two separate pathways leading to the same sulfoxide product [Met(O)] go through prohibitively high barriers of 27.3 and 35.1 kcal/mol, therefore it is ruled out. In the concerted mechanism, the Cu ²⁺ -Aβ complex has been found to be the most efficient catalyst with the computed barrier of 14.3 kcal/mol. The substitutions of Cu ²⁺ by Zn ²⁺ and Fe ³⁺ increase barriers to 19.6 and 16.9 kcal/mol, respectively and make the reaction thermodynamically less favorable. It was also found that, in comparison with the cysteine (Cys) residue, Met is more susceptible toward oxidation. Its substitution with Cys slightly increased the barrier to 15.8 kcal/mol for the Cu ²⁺ -Aβ complex.