Effect of the N-terminal basic residue on facile Cα–C bond cleavages of aromatic-containing peptide radical cations

Fragmentation of radical cationic peptides [R(G)n−2X(G)7−n]˙+ and [R(G)m−2XG]˙+ (X = Phe or Tyr; m = 2–5; n = 2–7) leads selectively to an+ product ions through in situ Cα–C peptide backbone cleavage at the aromatic amino acid residues. In contrast, substituting the arginine residue with a less-basic lysine residue, forming [K(G)n−2X(G)7−n]˙+ (X = Phe or Tyr; n = 2–7) analogs, generates abundant b–y product ions; no site-selective Cα–C peptide bond cleavage was observed. Studying the prototypical radical cationic tripeptides [RFG]˙+ and [KFG]˙+ using low-energy collision-induced dissociation and density functional theory, we have examined the influence of the basicity of the N-terminal amino acid residue on the competition between the isomerization and dissociation channels, particularly the selective Cα–C bond cleavage via β-hydrogen atom migration. The dissociation barriers for the formation of a2+ ions from [RFG]˙+ and [KFG]˙+via their β-radical isomers are comparable (33.1 and 35.0 kcal mol−1, respectively); the dissociation barrier for the charge-induced formation of the [b2 − H]˙+ radical cation from [RFG]˙+via its α-radical isomer (39.8 kcal mol−1) was considerably higher than that from [KFG]˙+ (27.2 kcal mol−1). Thus, the basic arginine residue sequesters the mobile proton to promote the charge-remote selective Cα–C bond cleavage by energetically hindering the competing charge-induced pathways.