The oxidation potential of thioethers constrained to be near aromatic rings is lowered, due to an antibonding interaction between the p-type sulfur lone pair with the neighboring phenyl π-system which on removal of an electron becomes a new kind of 3-electron S\π bonding that reveals itself in the photoelectron spectrum and by an electronic transition involving the orbitals participating in the S\π bond.Methionine is one of the most easily oxidized amino acids, and its thioether functional group has a high susceptibility to be attacked by free radicals. 1 It has been suggested to play a role in the pathogenesis of neurodegenerative diseases such as Parkinson's 2 and Alzheimer's 3 disease. Also, methionine has been postulated to be involved in long-range electron transfer through proteins using a multistep hopping process, 4 a process that is, however, not thermodynamically feasible unless the incipient thioether radical cations are stabilized by some neighboring moieties.An unusual property of the radical cations of dialkyl sulfides is their propensity to form two-center, threeelectron bonds with the nonbonding electrons of the neutral precursor, or with those of another heteroatom 5 (X in Scheme 1, left side). Such complexes distinguish themselves by broad σfσ* absorption bands which usually lie in the visible range. 5a Using model compounds where a methylthio and an amide moiety are attached to a norbornane skeleton, it was shown that such [S\X] complexation leads indeed to a decrease of the oxidation potential of the thioether, 6 as shown in Scheme 1. Hence, such interaction may account for the enhanced rate of electron transfer in model peptides where such interactions are possible.This paper provides experimental evidence that this propensity of sulfur radical cations to stabilize themselves by interacting with neighboring lone pairs can be extended † The University of Fribourg. ‡ The University of Arizona.(1) (a) Vogt, W. Free Radical Biol. Med. 1995, 18, 93-105. (b) Bobrowski, K.; Houee-Levin, C.; Marciniak, B. Chimia 2008, 62, 728-734. (2) Wassef, R.; Haenold, R.; Hansel, A.; Brot, N.; Heinemann, S. H.; Hoshi, T.
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.
Electron transfer over long distances in proteins by a hopping process requires transient relay stations that can harbor charge and spin for a short time span. Certain easily oxidizable or reducible side chains may assume that role, but it has been shown that charge transport in peptides can also take place in the absence of such groups which implies that the peptide backbone provides for hopping stations. We have identified three different types of radical cation states in such peptides that are associated with significantly lower ionization potentials than those of the constituent amino acids, and which may thus serve as relay stations for hole transport. Which of these states is the most stable one depends on the nature and the conformation of the peptide. In contrast to α-helices which, due to their high dipole moments, can only form stable radical cation states that are localized on the C-terminal amino acids, polyprolines are capable of accommodating such states inside the PPII helices and those states may serve as relay stations for hole transfer through polyprolines. Of which type these states are depends often on small conformational changes, and sometimes the most stable states are hybrids of the three types we have identified. ■ INTRODUCTIONThe transport of positive or negative charges over long distances is an essential function in living organisms. 1−3 For distances greater than ca. 2 nm, electron transfer in proteins can only occur in a multistep hopping process via "stepping stones" that are transiently oxidized or reduced during the process. 4,5 These relay stations allow one long and therefore very slow single step electron transfer to be divided into several short but quick steps which make that the rate of the electron transfer via multistep hopping decreases only slightly with the total distance between the electron donor and acceptor. 6,7 Several protein side groups were shown to be able to act as stepping stones in the course of hole transfer in proteins. They can be divided into two groups, the aromatic moieties in tyrosine, tryptophan, and imidazole, and the sulfur containing side chains in cysteine or methionine. The efficiency of the first group to serve as stepping stones is due to their low oxidation or reduction potentials, respectively. 8−10 Methionine on the other hand can only serve as a hole stepping stone if the oxidized sulfur lone pair is stabilized by a nearby aromatic or amide moiety. 11−14 It was also shown that, even in the absence of the above-mentioned side groups, the backbones of α-and 3 10 -helices or β-turns can serve as relay stations. In the case of these structures, a large dipole moment decreases the oxidation potential especially at the C-termini of such structures. 6,15−17 Another secondary structure is the so-called PPII helix which is found in most peptides including electron transport proteins like cytochrome C551 of Pseudomonas aeruginosa or bacteriochlorophyll A in the photosynthetic bacterium Prosthecochloris aestuarii. 18 A major component of...
Electronic absorption spectra and quantum chemical calculations of the radical cations of m-terphenyl tert-butyl thioethers, where the S-t-Bu bond is forced to be perpendicular to the central phenyl ring, show the occurrence of through-space [π···S···π](+) bonding interactions which lead to a stabilization of the thioether radical cations. In the corresponding methyl derivatives there is a competition between delocalization of the hole that is centered on a p-AO of the S atom into the π-system of the central phenyl ring or through space into the flanking phenyl groups, which leads to a mixture of planar and perpendicular conformations in the radical cation. Adding a second m-terphenyl tert-butyl thioether moiety does not lead to further delocalization; the spin and charge remain in one of the two halves of the radical cation. These findings have interesting implications with regard to the role of methionines as hopping stations in electron transfer through proteins.
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