We are conducting a theoretical investigation into the relative sensitivities of free-radical induced damage by hydrogen abstraction to the alpha carbon site of various amino acid residues in proteins.
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Toward Site Specificity of Oxidative Damage in Proteins: C-H and C-C Bond Dissociation Energies and the Reduction Potentials of the Radicals of Alanine, Serine, and Threonine - an Ab Initio Study
A. Rauk, D. Yu, and D. A. Armstrong, J. Am. Chem. Soc. in press (accepted 96/10/19)
Abstract: High level ab initio computations were used to characterise the parent species and radicals for alanine, serine and threonine, both as free neutral amino acids (AH) and as residues in model peptides (PH) intended to mimic the mid chain environment in proteins. The ab initio energies were used in isodesmic reactions to predict bond dissociation energies (BDEs, ) at 298 K, in kJ mol-1 to an estimated accuracy of 10 kJ mol-1. For the fully optimized systems the values of are: AH(Gly), 331; AH(Ala), 317; AH(Ser), 327; AH(Thr), 328; PH(Gly), 348; PH(Ala), 344; PH(Ser), 348; PH(Thr), 356. All of the values are less than the BDE of a typical SH bond (370 kJ mol-1), as in cysteine or glutathione (GSH), a result that suggests that oxidative damage at the site will not be repaired efficiently by the mechanism of H donation from GSH. Values of in typical peptide conformations, such as -sheet and -helical secondary structure, were estimated by constraining the Ramachandran dihedral angles phi, and psi, to values typical of these structures. Thus values are estimated as: PH(Gly), 361; PH(Ala), 359; PH(Ser), 347; PH(Thr), 356 in the beta-sheet conformation, and: PH(Gly), 402; PH(Ala), 384; PH(Ser), 381; PH(Thr), 363 in the alpha-helix conformation. Hence, these residues are also expected to be susceptible to irreparable oxidative damage in beta-sheet structures, but Gly, Ala and Ser residues in alpha-helical regions should be less susceptible to damage and should be repairable by GSH. A consideration of reduction potentials calculated from the BDEs and entropies derived from the ab initio results leads to the same conclusions and indicates that certain radicals other than OH. that occur in cells (e.g. ROO.) may also cause oxidative damage to beta-sheet structures. Ab initio calculations were also done for the C-centered radicals formed by removal of H from the side chains. These showed that there is a marked increase in the ease of abstraction of this H in the series Ala, Ser,Thr.