Proline as a charge stabilizing amino acid in peptide radical cations

Long distance electron transfer in proteins requires relay stations that can be transitorily oxidized or reduced. Although individual prolines cannot assume this function, because of their high ionization energy, it has been shown that polyprolines have the ability to transfer charges. In order to determine the role of the proline in the hole distribution and transport within a PheProPhe tripeptide, the radical cation of a model compound where the phenylalanines carry two or three methoxy groups, respectively, was generated by flash photolysis. Surprisingly, after equilibration, about two thirds of the holes were found to reside on the phen(OMe)₂ instead of the more easily oxidizable phen(OMe)₃ moiety. DFT calculations showed that, in most of the accessible conformations, the phen(OMe)₂^{? +}‐moiety profits more from stabilization by N‐ and/or O‐lone pairs of neighboring amide groups than the phen(OMe)₃^{? +} moiety can, which explains the apparently counterthermodynamic hole distribution. Similar calculations showed that, in several conformers of the natural PheProPhe radical cation, the unpaired electron is delocalized over two amide groups, by residing in a σ MO which links the N‐lone pair of the central proline unit with the O‐lone pair of a proximate amino acid, through hyperconjugation via the intervening C―C_α σ‐bond. The same pattern is found in a model compound, N‐acetylproline dimethylamide. It seems that prolines favor conformers which foster hyperconjugation of two amide groups, which lowers the ionization energy of peptides. One should thus consider such interacting amide groups as potential relay stations in the course of electron transfer in polyprolines. Copyright © 2015 John Wiley & Sons, Ltd.