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 glycyl proteins 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. Key words: glycine, peptide, amino acid, bond energy, radicals, ab initio, computation.

Oxidative Degradation of Thiaproline Derivatives in Aqueous Solutions Induced by •OH Radicals

“…[27] Thus errors due to the basis set and correlation effects are reduced. The reaction in Equation (7) ) was calculated with a high accuracy by Armstrong et al [28] Rð n CCÞ þ AH ! Rð n CÀHÞ þ AC ð7Þ…”

In silico evaluation of proposed biosynthetic pathways for the unique dithiolate ligand of the H‐cluster of [FeFe]‐hydrogenase

“…This is attributed to the presence of both electron-withdrawing and electron-donating substituents adjacent to a single radical center (captodative effect). [47,55] However, the coupling of Gly to the fully oxidized [2Fe-2S] 2þ cluster, although slightly exothermic by 9 kJ mol À1 , is nonspontaneous by 38 kJ mol À1 in contrast to the respective sulfur alkylation step where N-methylpropanamine was considered as the initial substrate (path A2, 1!2). Gly is not reactive enough to compensate for the loss of the stabilizing super-exchange interactions within the cluster that are weakened when one l-S 3p orbital is tied up in the formation of a CAS bond.…”

Anaerobic functionalization of unactivated C–H bonds

“…It is interesting that nature would elect to employ a glycyl radical-based mechanism for alkylsuccinate synthases, given the unfavorable equilibrium associated with a glycyl radical ultimately generating a secondary alkyl radical—although via a thiyl radical intermediate. Glycyl and cysteinyl residues possess gas-phase HBDEs of ∼83 (C α –H) and 90 (S–H) kcal/mol, respectively [39,40], while C–H bonds on secondary carbons possess HBDEs of ∼95 kcal/mol [40]. Therefore, the equilibrium would be expected to lie considerably to the left in the absence of significant influence by the active site of the enzyme.…”