The role of basic residues in the fragmentation process of the lysine rich cell-penetrating peptide TP10.

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Selective cleavage effect of basic residues in the fragmentation of short peptides has been studied intensively. In contrast, the role of basic residues in the degradation of large peptides, such as cell-penetrating peptides, is largely unknown. In this work, the fragmentation of a 21 residues cell-penetrating peptide TP10 containing four lysine residues was studied by collision-induced dissociation mass spectrometry and computation methods. The influence of lysine residues on amide bond cleavage and fragmentation products was investigated. The results revealed that the selective cleavage effect of lysine residue did not present when the adjacent lysine residues in TP10 were both protonated. The localized high positive charge density might be the reason of preventing the mobile proton from migrating to the amide bonds in this part of the peptide. In contrast, the mobile proton preferred to reside in the N-terminal part of TP10 which had less positive charge. This preference gave more information of the peptide sequence in the mass spectrometry study and was helpful for stabilizing the C-terminal part of TP10, in which the basic lysine residues were preserved and crucial to the cell-penetrating process.