Copper-Mediated Peptide Radical Ions in the Gas Phase

Abstract

Molecular radical cations, M •+ , of amino acids and oligopeptides are produced by collision-induced dissociation of mixed complex ions, [Cu II (dien)M] •2+ , that contain Cu II , an amine, typically diethylenetriamine (dien), and the oligopeptide, M. With dien as the amine ligand, abundant M •+ formation is observed only for the amino acids tryptophan and tyrosine, and oligopeptides that contain either the tryptophanyl or tyrosyl residue. Dissociation of the M •+ ion is rich and differs considerably from that of protonated amino acids and peptides. Facile fragmentation occurs around the R-carbon of the tryptophanyl residue. Cleavage of the N-C R bond and proton transfer from the exocyclic methylene group in the side chain to the N-terminal residue results in formation of the [z n -H] •+ ion and elimination of the N-terminal fragment as ammonia or an amide, depending on the position of the tryptophanyl residue. Cleavage of the C R -C bond of an oligopeptide containing a C-terminal tryptophan residue and proton transfer from the carboxylic group to the N-terminal fragment (a carbonyl oxygen atom) results in formation of the [a n + H] •+ ion and elimination of carbon dioxide. Both types of fragmentation have no analogous reactions in protonated peptides. For the M •+ of tryptophanylglycylglycine, WGG, elimination of the tryptophanyl side chain results in GGG •+ . This radical cation fragments by eliminating its C-terminal glycine to give the [b 2 -H] •+ ion, which is an oxazolone and shares much of the structure and reactivity of the b 2 + ion from protonated triglycine. Density functional theory shows the mechanism of forming the [b 2 -H] •+ ion is similar to that of the b 2 + ion, although the free-energy barrier at 29.4 kcal/mol is lower. The [b 2 -H] •+ ion eliminates CO readily to give the [a 2 -H] •+ ion, which is an iminium radical ion.

Kinetics for tautomerizations and dissociations of triglycine radical cations

“…UV photodissociation of a peptide/protein chemically modified to incorporate an appropriate chromophore can generate a radical cation that undergoes site-specific, radical-driven dissociations, which are useful in protein identifications [25,26]. Peptide radical cations have also been generated via low-energy CID of a ternary metal complex containing the peptide and auxiliary ligands [27][28][29][30][31][32][33][34][35][36][37]. These methodologies open new avenues whereby the fragmentation chemistries of peptide radical cations can be examined and exploited.…”

“…These fragmentations are useful in providing differentiating signatures for isobaric residues present [14, 29, 38 -40], e.g., between leucine and isoleucine [14,29], and between aspartic acid and isoaspartic acid [38,39]. For aromatic amino acid residues, cleavage of the C ␣ -C ␤ bond eliminates pquinomethide from tyrosine and 3-methylene indolenine from tryptophan, yielding a glycyl radical with the unpaired electron located on the ␣-carbon [12,27,28,30]. Such ␣-centered radicals have been identified in some anaerobic enzymes [41][42][43], including pyruvate formatelyase [44,45], anaerobic ribonucleotide reductase [46], benzylsuccinate synthase [47,48], 4-hydroxyphenylacetate decarboxylase [49], and glycerol dehydratase [50].…”

Experimental and computational studies of the macrocyclic effect of an auxiliary ligand on electron and proton transfers within ternary copper(II)-Histidine complexes

“…Oxidized radical products from Cu(II)-protein ion complexes have been proposed as intermediates that play key roles in several neurodegenerative conditions, including Alzheimer's disease (␤-amyloid peptide) and bovine spongiform encephalitis (prion protein) [3,4]. It was demonstrated recently that the dissociation of ligated Cu(II)-peptide complexes [Cu II (L)M] •2ϩ (L, ligand; M, peptide) generates peptide radical cations (M •ϩ ) through ET dissociation in the gas phase [7][8][9][10][11][12][13][14][15][16][17][18]. Such complexes are a useful simple system for studying the fundamental parameters that govern the formation of peptide radical cations through single-electron transfer in the absence of solvation.…”

“…The experimental results can be further examined in conjunction with theoretical calculations. Several systematic studies have been performed to determine the roles played by the auxiliary ligands and metals during the formation of peptide radical cations through ET dissociation (Reaction 1) [7][8][9][10][11][12][13][14][15][16]. Three major competitive dissociation pathways have been reported: proton transfer (PT) to the peptide (Reaction 2) [7-12, 14, 16, 19 -21], proton abstraction from the peptide (Reaction 3) [7,8,10,11,22], and peptide fragmentation (Reaction 4) [7-12, 14, 19, 20, 23, 24].…”

“…Studies into the dissociation of [Cu II (dien)M] •2ϩ complexes (dien: diethylenetriamine) have indicated that ET reactions predominate only for peptides containing tryptophan or tyrosine residues, which have relatively low ionization energies; other peptides dissociate preferably through PT reactions, especially for peptides containing basic amino residues [7][8][9]. PT can be moderated by using ligands such as N,N,N=,N=,NЉ-pentamethyldiethylenetriamine (Me 5 dien) and 2,2=:6=,2Љ-terpyridine (terpy).…”