Effect of Side Chains on Competing Pathways for β-Scission Reactions of Peptide-Backbone Alkoxyl Radicals

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Abstract

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 1012 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 (107 s-1) to very fast (1012 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 < Gln ∼ 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 ∼30 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.

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