Effect of side chains on competing pathways for β-scission reactions of peptide-backbone alkoxyl radicals

High-level quantum chemistry calculations have been carried out to investigate β-scission reactions of alkoxyl radicals located at the α-carbon of a peptide backbone. This type of alkoxyl radical may undergo three possible β-scission reactions, namely C-C β-scission of the backbone, C-N β-scission of the backbone, and C-R β-scission of the side chain. We find that the rates for the C-C β-scission reactions are all very fast, with rate constants of the order 10 ¹² s ^-1 that are essentially independent of the side chain. The C-N β-scission reactions are all slow, with rate constants that range from 10 ^-0.7 to 10 ^-4.5 s ^-1. The rates of the C-R β-scission reactions depend on the side chain and range from moderately fast (10 ⁷ s ^-1) to very fast (10 ¹² s ^-1) The rates of the C-R β-scission reactions correlate well with the relative stabilities of the resultant side-chain product radicals (R), as reflected in calculated radical stabilization energies (RSEs). The order of stabilities for the side-chain fragment radicals for the natural amino acids is found to be Ala < Glu < Gin ∼ Leu ∼ Met ∼ Lys ∼ Arg < Asp ∼ Ile ∼ Asn ∼ Val < Ser ∼ Thr ∼ Cys < Phe ∼ Tyr ∼ His ∼ Trp. We predict that for side-chain C-R β-scission reactions to effectively compete with the backbone C-C β-scission reactions, the side-chain fragment radicals would generally need an RSE greater than β30 kJ mol ^-1. Thus, the residues that may lead to competitive side-chain β-scission reactions are Ser, Thr, Cys, Phe, Tyr, His, and Trp.