Arginine-facilitated isomerization: Radical-induced dissociation of aliphatic radical cationic glycylarginyl(iso)leucine tripeptides

The gas phase fragmentations of aliphatic radical cationic glycylglycyl(iso)leucine tripeptides ([G•G(L/I)]⁺), with well-defined initial locations of the radical centers at their N-terminal α-carbon atoms, are significantly different from those of their basic glycylarginyl(iso)leucine ([G•R(L/I)]⁺) counterparts; the former lead predominantly to [b₂ - H]^•+ fragment ions, whereas the latter result in the formation of characteristic product ions via the losses of •CH(CH₃)₂ from [G•RL]⁺ and •CH₂CH₃ from [G•RI]⁺ through C_β-C_γ side-chain cleavages of the (iso)leucine residues, making these two peptides distinguishable. The α-carbon-centered radical at the leucine residue is the key intermediate that triggers the subsequent C_β-C_γ bond cleavage, as supported by the absence of •CH(CH₃)₂ loss from the collision-induced dissociation of [G•RL_α-Me]⁺, a radical cation for which the α-hydrogen atom of the leucine residue had been substituted by a methyl group. Density functional theory calculations at the B3LYP 6-31++G(d,p) level of theory supported the notion that the highly basic arginine residue could not only increase the energy barriers against charge-induced dissociation pathways but also decrease the energy barriers against hydrogen atom transfers in the GR(L/I) radical cations by ∼10 kcal mol^-1, thereby allowing the intermediate precursors containing α- and γ-carbon-centered radicals at the (iso)leucine residues to be formed more readily prior to promoting subsequent C_β-C _γ and C_α-C_β bond cleavages. The hydrogen atom transfer barriers for the α- and γ-carbon-centered GR(L/I) radical cations (roughly in the range 29-34 kcal mol^-1) are comparable with those of the competitive side-chain cleavage processes. The transition structures for the elimination of •CH(CH₃) ₂ and •CH₂CH₃ from the (iso)leucine side chains possess similar structures, but slightly different dissociation barriers of 31.9 and 34.0 kcal mol^-1, respectively; the energy barriers for the elimination of the alkenes CH₂=CH(CH₃)₂ and CH₃CH=CHCH₃ through C_α-C _β bond cleavages of γ-carbon-centered radicals at the (iso)leucine side chains are 29.1 and 32.8 kcal mol^-1, respectively. © 2012 American Chemical Society.