Influence of beta-sheet structure on the susceptibility of proteins to backbone oxidative damage: Preference for C-alpha-centered radical formation at glycine residues of antiparallel beta-sheets

Ab initio calculations at the B3LYP/6-31G(d) level of theory were carried o ut on selected cyclic hydrogen-bonded (H-bonded) dimers of glycine and alan ine as models for beta-sheets and on the C-alpha-centered radicals derived from them. The structures mirrored the cycles found in the II-bonded networ k of parallel and antiparallel beta-sheet secondary structure, and were oti mized both with and without enforcement of constraints on the Phi,Psi torsi on angles. Transition structures for the migration of an H atom from an UC site to another C-alpha site or to an S atom were located. It was found tha t the presence of a H-bonded strand of a beta-sheet has little effect on th e C-alpha-H bond dissociation enthalpy (BDE) of glycine but raises the BDE of other residues by a significant amount. The parallel beta-sheet structur e and Phi,Psi angles lead to a significant increase in BDE, relative to the random coil structure, due to loss of captodative stabilization. The antip arallel beta-sheet structure and Phi,Psi angles do not lead to a significan t increase in BDE. All residues incorporated in beta-sheet secondary struct ure, with the exception of glycine, are protected from oxidative damage bec ause the C-alpha-H bond is internal to the sheet and inaccessible to oxidiz ing radicals. Glycine is susceptible to oxidative damage because it has a s econd C-alpha-H bond which is exposed. Among residues in secondary structur es, only glycine is susceptible to damage by weak oxidants such as thiyl ra dicals and superoxide, provided it is in an antiparallel beta-sheet. Radica l damage may propagate readily from one strand to another above the beta-sh eet, but not within the beta-sheet. beta-Sheet structure narrows the differ ence between the glycyl C-alpha-H BDE and S-H BDE and facilitates interstra nd H atom transfer between the glycyl C-alpha site and the S atom of cystei ne.