Influence of β-Sheet Structure on the Susceptibility of Proteins to Backbone Oxidative Damage: Preference for αC-Centered Radical Formation at Glycine Residues of Antiparallel β-Sheets

Ab initio calculations at the B3LYP/6-31G(d) level of theory were carried out on selected cyclic hydrogen-bonded (H-bonded) dimers of glycine and alanine as models for β-sheets and on the α C-centered radicals derived from them. The structures mirrored the cycles found in the H-bonded network of parallel and antiparallel β-sheet secondary structure, and were otimized both with and without enforcement of constraints on the Φ,Ψ torsion angles. Transition structures for the migration of an H atom from an α C site to another α C site or to an S atom were located. It was found that the presence of a H-bonded strand of a β-sheet has little effect on the α C−H bond dissociation enthalpy (BDE) of glycine but raises the BDE of other residues by a significant amount. The parallel β-sheet structure and Φ,Ψ angles lead to a significant increase in BDE, relative to the random coil structure, due to loss of captodative stabilization. The antiparallel β-sheet structure and Φ,Ψ angles do not lead to a significant increase in BDE. All residues incorporated in β-sheet secondary structure, with the exception of glycine, are protected from oxidative damage because the α C−H bond is internal to the sheet and inaccessible to oxidizing radicals. Glycine is susceptible to oxidative damage because it has a second α C−H bond which is exposed. Among residues in secondary structures, only glycine is susceptible to damage by weak oxidants such as thiyl radicals and superoxide, provided it is in an antiparallel β-sheet. Radical damage may propagate readily from one strand to another above the β-sheet, but not within the β-sheet. β-Sheet structure narrows the difference between the glycyl α C−H BDE and S−H BDE and facilitates interstrand H atom transfer between the glycyl α C site and the S atom of cysteine.