Ab initio studies on the mechanism of tyrosine coupling

Oxidative stress is considered to be a major contributor to dysfunction in a host of disease states. Reactive oxygen species (ROS) mediate distinct ox idative alterations in biopolymers, including DNA, proteins, lipids, and li poproteins. Currently, the mechanisms of biochemical reactions underlying o xidative stress are poorly understood because of the instability of ROS. On e of the consequences of oxidative stress is one-electron oxidation of tyro sine (Tyr) residues in proteins, which represents a hallmark of this insult and is implicated in the pathogenesis of a number of pathological processe s leading to atherosclerosis, inflammatory conditions, multiple system atro phy and several neurodegenerative diseases. Major products of oxidation of Tyr include protein-bound dityrosine and isodityrosine. In this report, the mechanism of tyrosine coupling (including structure and stability of a num ber of proposed reaction intermediates) is studied by high-level density fu nctional and conventional ab initio methods including B3LYP, MP2, CASSCF, a nd CASPT2. It is demonstrated that dityrosine and isodityrosine are the mos t stable structures at all theoretical levels applied. In addition to class ical structures of the reaction intermediates, evidence is found for a nove l transient structure of Tyr dimer, stacked dityrosyl. This dimer is predic ted to exist because of strong electron correlation between two tyrosyl moi eties. The counterpoise corrected energy of stacked dityrosyl is below the energy of two tyrosyl radicals by about 95 kJ/mol at the PUMP2/6-31** level . High proton affinity of tyrosyl radical (about 9.4 eV) suggests that posi tively charged amino acids in the vicinity of a solvent-exposed Tyr residue may increase the probability of tyrosine coupling.