Computational study on the attack of ·OH radicals on aromatic amino acids

The attack of hydroxyl radicals on aromatic amino acid side chains, namely phenylalanine, tyrosine, and tryptophan, have been studied by using density functional theory. Two reaction mechanisms were considered: 1) Addition reactions onto the aromatic ring atoms and 2) hydrogen abstraction from all of the possible atoms on the side chains. The thermodynamics and kinetics of the attack of a maximum of two hydroxyl radicals were studied, considering the effect of different protein environments at two different dielectric values (4 and 80). The obtained theoretical results explain how the radical attacks take place and provide new insight into the reasons for the experimentally observed preferential mechanism. These results indicate that, even though the attack of the first (·)OH radical on an aliphatic C atom is energetically favored, the larger delocalization and concomitant stabilization that are obtained by attack on the aromatic side chain prevail. Thus, the obtained theoretical results are in agreement with the experimental evidence that the aromatic side chain is the main target for radical attack and show that the first (·)OH radical is added onto the aromatic ring, whereas a second radical abstracts a hydrogen atom from the same position to obtain the oxidized product. Moreover, the results indicate that the reaction can be favored in the buried region of the protein.