OXIDATIVE DAMAGE TO AND BY CYSTEINE IN PROTEINS - AN AB-INITIO STUDY OF THE RADICAL STRUCTURES, C-H, S-H, AND C-C BOND-DISSOCIATION ENERGIES, AND TRANSITION STRUCTURES FOR H ABSTRACTION BY THIYL RADICALS

Ab initio computations (B3LYP/6-31G(D), coupled with isodesmic reactio ns) were used to predict bond dissociation energies (BDEs) of C-alpha- H (D-alpha CH) and other bonds of cysteine, both as free neutral amino acid (AH(Cys)) and as a residue in a model peptide (PH(Cys)). The lat ter was intended to mimic the environment in proteins. Transition stru ctures were located for intermolecular and intramolecular H atom trans fer to a thiyl radical (RS.) from a sulfhydryl group (RSH) or the UC-H bond. The predicted BDEs, at 298 K, in kJ mol(-1) to an estimated acc uracy of 10 kJ mol(-1) for the fully optimized system are (AH(Cys)) D- alpha CH = 322, D-beta CH = 390, D-alpha CC = 264, and D-SH = 373 and (PH(Cys)) D-alpha CH = 346, D-beta CH = 392, D-alpha CC = 287, and D-S H = 367. In PH(Cys) with torsional angles constrained to simulate beta -sheet and alpha-helical secondary structure, D-alpha CH rises to 359 and 376, respectively. Cystine in the peptide environment was modeled by replacing -SH by -SSCH3, PH(CysSCH(3)), D-alpha CH = 330. Enthalpie s of activation for intermolecular H transfer to RS. were found to be low: from RSH, 12 kJ mol(-1); from C-alpha-H, about 25 kJ mol(-1), the latter being consistent with reaction rates on the order of 10(5) M-1 s(-1). The enthalpic barrier for intramolecular H transfer from C-alp ha-H to -S-. within a single cysteine residue is too high (83-111 kJ m ol(-1)) for this to be a competitive process.