Oxidative damage to the glycyl α-carbon site in proteins: An ab initio study of the C-H bond dissociation energy and the reduction potential of the C-centered radical

Abstract

The C - H bond dissociation energies (DC - H) of a series of model glycylproteins were derived from selected isodesmic reactions based on high level ab initio calculations. At 298 K, the recommended values of DC - H, in kJ mol-1 are: NH2CH2CHO, 308; NH2CH2C(O)NH2, 336; HC(O)NHCH2CHO, 331; HC(O)NHCH2C(O)NH2, 350; CH3C(O)NHCH2C(O)NH2, 347; HC(O)NHCH2C(O)NHCH3, 349; and CH3C(O)NHCH2C(O)NHCH3, 346. The average of the last four values, 348 kJ mol-1, is the predicted bond dissociation energy of the α-C - H bond of a glycyl protein. The reduction potential in aqueous medium at 298 K and pH 7 for the process, R· + H+ + e- = RH, where R· = XNHCH·C(O)Y and X and Y represent extension of the protein chain, is E0′ = 0.8 V. This result suggests that the α-C - H bond of a glycyl protein is susceptible to attack by RS·, ROO·, tyrosyl, and OH· radicals, whose reduction potentials for the analogous process are higher. The present study has established that the molecule HC(O)NHCHRC(O)NH2 (R = an amino acid side chain) serves as an accurate model for the α-C environment of an amino acid residue in a protein, and that a reliable DC - H value for the α-C - H bond may be obtained from calculations on this model at the B3LYP/6-31G(D) level of theory in conjunction with an isodesmic reaction using neutral glycine as reference.