Cation Recombination Energy/Coulomb Repulsion Effects in ETD/ECD as Revealed by Variation of Charge per Residue at Fixed Total Charge

Electron capture dissociation (ECD) and electron transfer dissociation (ETD) experiments in electrodynamic ion traps operated in the presence of a bath gas in the 1–10 mTorr range have been conducted on a common set of doubly protonated model peptides of the form X(AG)_nX (X = lysine, arginine, or histidine, n?=?1, 2, or 4). The partitioning of reaction products was measured using thermal electrons, anions of azobenzene, and anions of 1,3-dinitrobenzene as reagents. Variation of n alters the charge per residue of the peptide cation, which affects recombination energy. The ECD experiments showed that H-atom loss is greatest for the n?=?1 peptides and decreases as n increases. Proton transfer in ETD, on the other hand, is expected to increase as charge per residue decreases (i.e., as n increases). These opposing tendencies were apparent in the data for the K(AG)_nK peptides. H-atom loss appeared to be more prevalent in ECD than in ETD and is rationalized on the basis of either internal energy differences, differences in angular momentum transfer associated with the electron capture versus electron transfer processes, or a combination of the two. The histidine peptides showed the greatest extent of charge reduction without dissociation, the arginine peptides showed the greatest extent of side-chain cleavages, and the lysine peptides generally showed the greatest extent of partitioning into the c/z?-product ion channels. The fragmentation patterns for the complementary c- and z?-ions for ETD and ECD were found to be remarkably similar, particularly for the peptides with X = lysine.

Electron transfer versus proton transfer in gas-phase ion/ion reactions of polyprotonated peptides

The ion/ion reactions of several dozen reagent anions with triply protonated cations of the model peptide KGAILKGAILR have been examined to evaluate predictions of a Landau-Zener-based model for the likelihood for electron transfer. Evidence for electron transfer was provided by the appearance of fragment ions unique to electron transfer or electron capture dissociation. Proton transfer and electron transfer are competitive processes for any combination of anionic and cationic reactants. For reagent anions in reactions with protonated peptides, proton transfer is usually significantly more exothermic than electron transfer. If charge transfer occurs at relatively long distances, electron transfer should, therefore, be favored on kinetic grounds because the reactant and product channels cross at greater distances, provided conditions are favorable for electron transfer at the crossing point. The results are consistent with a model based on Landau-Zener theory that indicates both thermodynamic and geometric criteria apply for electron transfer involving polyatomic anions. Both the model and the data suggest that electron affinities associated with the anionic reagents greater than about 60-70 kcal/mol minimize the likelihood that electron transfer will be observed. Provided the electron affinity is not too high, the Franck-Condon factors associated with the anion and its corresponding neutral must not be too low. When one or the other of these criteria is not met, proton transfer tends to occur essentially exclusively. Experiments involving ion/ion attachment products also suggest that a significant barrier exists to the isomerization between chemical complexes that, if formed, lead to either proton transfer or electron transfer.     

Gas-phase peptide fragmentation: how understanding the fundamentals provides a springboard to developing new chemistry and novel proteomic tools

This tutorial provides an overview of the evolution of some of the key concepts in the gas-phase fragmentation of different classes of peptide ions under various conditions [e.g. collision-induced dissociation (CID) and electron transfer dissociation (ETD)], and then demonstrates how these concepts can be used to develop new methods. For example, an understanding of the role of the mobile proton and neighboring group interactions in the fragmentation reactions of protonated peptides has led to the design of the 'SELECT' method. For ETD, a model based on the Landau-Zener theory reveals the role of both thermodynamic and geometric effects in the electron transfer from polyatomic reagent anions to multiply protonated peptides, and this predictive model has facilitated the design of a new strategy to form ETD reagent anions from precursors generated via ESI. Finally, two promising, emerging areas of gas-phase ion chemistry of peptides are also described: (1) the design of new gas-phase radical chemistry to probe peptide structure, and (2) selective cleavage of disulfide bonds of peptides in the gas phase via various physicochemical approaches.     

Charge inversion via concurrent cation and anion transfer: application to corticosteroids

A novel charge inversion process that involves the removal of an excess cation from an analyte ion and the transfer of an anion to the neutral analyte in a single ion/ion encounter is described. Polyamidoamine (PAMAM) half-generation dendrimer anions that contain small anions, such as the chloride ion, were used as charge inversion reagents. Several competing processes can occur that include removal of the cation to neutralize the analyte, the removal of the excess cation and an additional proton to yield the deprotonated molecule, or removal of the excess cation and transfer of a small anion to the analyte. For the latter process to dominate, several requirements for both the reagent anion and the analyte cation must be met. The reagent anion must form multiply charged anions and must be able to incorporate one or more small anions for transfer. The analyte must have no strongly acidic sites as well as a relatively high affinity for small anion attachment. The PAMAM dendrimer anions must meet the conditions for the reagent anions and the cations of the corticosteroids meet the conditions for the analyte. The estrogenic steroid estrone, on the other hand, does not meet the requirements and, as a result, is largely neutralized when reacted with the reagent anions. This reaction, therefore, is highly selective and might serve as a useful reaction for the screening of appropriate analytes.     

Competitive benzyl cation transfer and proton transfer: collision‐induced mass spectrometric fragmentation of protonated N,N‐dibenzylaniline

Collision‐induced dissociation of protonated N ,N ‐dibenzylaniline was investigated by electrospray tandem mass spectrometry. Various fragmentation pathways were dominated by benzyl cation and proton transfer. Benzyl cation transfers from the initial site (nitrogen) to benzylic phenyl or aniline phenyl ring. The benzyl cations transfer to the two different sites, and both result in the benzene loss combined with 1,3‐H shift. In addition, after the benzyl cation transfers to the benzylic phenyl ring, 1,2‐H shift and 1,4‐H shift proceed competitively to trigger the diphenylmethane loss and aniline loss, respectively. Deuterium labeling experiments, substituent labeling experiments and density functional theory calculations were performed to support the proposed benzyl cation and proton transfer mechanism. Overall, this study enriches the knowledge of fragmentation mechanisms of protonated N ‐benzyl compounds. Copyright © 2017 John Wiley & Sons, Ltd.     

Toward a general mechanism of electron capture dissociation

The effects of positive charge on the properties of ammonium and amide radicals were investigated by ab initio and density functional theory calculations with the goal of elucidating the energetics of electron capture dissociation (ECD) of multiply charged peptide ions. The electronic properties of the amide group in N-methylacetamide (NMA) are greatly affected by the presence of a remote charge in the form of a point charge, methylammonium, or guanidinium cations. The common effect of the remote charge is an increase of the electron affinity of the amide group, resulting in exothermic electron capture. The N-Calpha bond dissociation and transition state energies in charge-stabilized NMA anions are 20-50 kJ mol(-1) greater than in the hydrogen atom adduct. The zwitterions formed by electron capture have proton affinities that were calculated as 1030-1350 kJ mol(-1), and are sufficiently basic for the amide carbonyl to exothermically abstract a proton from the ammonium, guanidinium and imidazolium groups in protonated lysine, arginine, and histidine residues, respectively. A new mechanism is proposed for ECD of multiply charged peptide and protein cations in which the electron enters a charge-stabilized electronic state delocalized over the amide group, which is a superbase that abstracts a proton from a sterically proximate amino acid residue to form a labile aminoketyl radical that dissociates by N-Calpha bond cleavage. This mechanism explains the low selectivity of N-Calpha bond dissociations induced by electron capture, and is applicable to dissociations of peptide ions in which the charge carriers are metal ions or quaternary ammonium groups. The new amide superbase and the previously proposed mechanisms of ECD can be uniformly viewed as being triggered by intramolecular proton transfer in charge-reduced amide cation-radicals. In contrast, remote charge affects N-H bond dissociation in weakly bound ground electronic states of hypervalent ammonium radicals, as represented by methylammonium, CH3NH3*, but has a negligible effect on the N-H bond dissociation in the strongly bound excited electronic states. This refutes previous speculations that loss of "hot hydrogen" can occur from an excited state of an ammonium radical.     

Structural character and energetics of tyrosyl radical formation by electron/proton transfers of a covalently linked histidine-tyrosine: a model for cytochrome C oxidase

The structural, energetic, and electronic and IR spectroscopic properties for a model of the cross-linked histidine-tyrosine (His-Tyr) residues as found in cytochrome c oxidase (CcO) are investigated by ab initio methods. The formation of a His-Tyr radical is studied by two paths: proton release followed by electron release and vice versa. The energetics for the proton/electron releases of the Tyr depend modestly on the cross-linked His substituent and, more sensitively, on the charge of the cation attached to the imino N site of the His residue. Protonation of the imino N site significantly increases the electron ionization potential and decreases the proton dissociation energy, making them competitive processes. A positive charge placed at the imino N site, whose value is scanned from zero to one, shows a continuous increase in ionization potential and a decrease in proton dissociation energy, with the +1 limit agreeing well with the protonated imino N site result, indicating a dominant electrostatic effect. The charge populations and the spin density distributions of the His-Tyr model, the radical cation formed by electron ionization, the anion formed by proton dissociation, and the final His-Tyr radical depend sensitively on the substituents, implying a modulation role on the charge transfer between the phenol and imidazole rings, especially for the charged species. His-Tyr and protonated His-Tyr exhibit differences among their respective structural isomers with consequences on their IR absorptions. Small barriers between their pseudo-cis and pseudo-trans rotamers demonstrate the relative flexibility between the two rings, and these may facilitate proton release and charge transfer. The cation effect demonstrates that the cationized cross-linked His-Tyr should be the best candidate to mimic the covalently ring-linked histidine-tyrosine structure in CcO.     

An investigation of the energetics of peptide ion dissociation by laser desorption chemical ionization fourier transform mass spectrometry

The energy dependence of competing fragmentation pathways of protonated peptide molecules is studied via laser desorption—chemical ionization in a Fourier transform ion cyclotron resonance spectrometer. Neutral peptide molecules are desorbed by the technique of substrate-assisted laser desorption, followed by post-ionization with a proton transfer reagent ion species. The chemical ionization reaction activates the protonated peptide molecules, which then fragment in accordance with the amount of excess energy that is deposited. Chemical ionization forms a protonated molecule with a narrower distribution of activation energy than can be formed by activation methods such as collision activated dissociation. Furthermore, the upper limit of the activation energy is well defined and is approximately given by the enthalpy of the chemical ionization reaction. Control over the fragmentation of peptide ions is demonstrated through reactions between desorbed peptide molecules with different reagent ion species. The fragmentation behavior of peptide ions with different internal energies is established by generation of a breakdown curve for the peptide under investigation. Breakdown curves are reported for the peptides Val-Pro, Val-Pro-Leu, Phe-Phe-Gly-Leu-Met NH₂, and Arg-Lys-Asp-Val-Tyr. The derived breakdown curve of Val-Pro has been fitted by using quasi-equilibrium Rice-Ramsperger-Kassel-Marcus theory to model the unimolecular dissociation of the protonated peptide to provide a better understanding of the mechanisms for the formation of fragment ions that originate from protonated peptides.     

Ion trap collision-induced dissociation of multiply deprotonated RNA: c/y-ions versus (a-B)/w-ions

The dissociation of model RNA anions has been studied as a function of anion charge state and excitation amplitude using ion trap collisional activation. Similar to DNA anions, the precursor ion charge state of an RNA anion plays an important role in directing the preferred dissociation channels. Generally, the complementary c/y-ions from 5′ P-O bond cleavage dominate at low to intermediate charge states, while other backbone cleavages appear to a limited extent but increase in number and relative abundance at higher excitation energies. The competition between base loss, either as a neutral or as an anion, as well as the preference for the identity of the lost base are also observed to be charge-state dependent. To gain further insight into the partitioning of the dissociation products among the various possible channels, model dinucleotide anions have been subjected to a systematic study. In comparison to DNA, the 2′-OH group on RNA significantly facilitates the dissociation of the 5′ P-O bond. However, the degree of excitation required for a 5′ base loss and the subsequent 3′ C-O bond cleavage are similar for the analogous RNA and DNA dinucleotides. Data collected for protonated dinucleotides, however, suggest that the 2′-OH group in RNA can stabilize the glycosidic bond of a protonated base. Therefore, base loss from low charge state oligonucleotide anions, in which protonation of one or more bases via intramolecular proton transfer can occur, may also be stabilized in RNA anions relative to corresponding DNA anions.     

Effect of the basic residue on the energetics, dynamics, and mechanisms of gas-phase fragmentation of protonated peptides

The effect of the basic residue on the energetics, dynamics, and mechanisms of backbone fragmentation of protonated peptides was investigated. Time-resolved and collision energy-resolved surface-induced dissociation (SID) of singly protonated peptides with the N-terminal arginine residue and their analogues, in which arginine is replaced with less basic lysine and histidine residues, was examined using a specially configured Fourier transform ion cyclotron resonance mass spectrometer (FTICR-MS). SID experiments demonstrated different kinetics of formation of several primary product ions of peptides with and without arginine residue. The energetics and dynamics of these pathways were determined from Rice-Ramsperger-Kassel-Marcus (RRKM) modeling of the experimental data. Comparison between the kinetics and energetics of fragmentation of arginine-containing peptides and the corresponding methyl ester derivatives provides important information on the effect of dissociation pathways involving salt bridge (SB) intermediates on the observed fragmentation behavior. Because pathways involving SB intermediates are characterized by low threshold energies, they efficiently compete with classical oxazolone and imine/enol pathways of arginine-containing peptides on a long time scale of the FTICR instrument. In contrast, fragmentation of histidine- and lysine-containing peptides is largely determined by canonical pathways. Because SB pathways are characterized by negative activation entropies, fragmentation of arginine-containing peptides is kinetically hindered and observed at higher collision energies as compared to their lysine- and histidine-containing analogues.     

Decompositions of cationized heterodimers of amino acids in relation to charge location in peptide ions

The unimolecular decompositions of protonated heterodimers of native and derivatized amino acids to yield the protonated monomers were studied as a guide to charge location in peptide ions. Analyses using a hybrid instrument of BEqQ geometry demonstrated the advantages (with respect to mass resolution, sensitivityr reproducibility, and the elimination of extraneous signals) of the detection of product ions formed in the radiofrequency-only quadrupole region (q) rather than in the field-free region between Band E. Conversion of arginine to dimethylpyrimidylomithine (DMPO) reduced the proton affinity, as evidenced by the decomposition of the protonated arginine/DMPO heterodimer. Conversion of cysteine to pyridylethylcysteine enhanced the proton affinity. Application of these derivatization procedures to peptides resulted in changes in the observed fragmentations of the protonated precursors consistent with the predicted modifications in charge location. Unimolecular decomposition of the protonated dimer composed of glycine and N-acetylglycine yielded both protonated monomers with abundances differing by a factor of only 2; this suggests that in protonated peptides, the amide bonds are competitive with the N-terminal amino group as sites of protonation. It is clear that the propensities to proton’ or metal-cation location at particular sites in peptides are influenced by both short- and long-range intraionic interactions. In peptides composed of amino acids of similar cation affinities, it may be postulated that the ion population is heterogeneous with respect to the site of charge, with consequent promotion of multiple low-energy fragmentation routes.     

N-centered odd-electron ions formation from collision-induced dissociation of electrospray ionization generated even-electron ions: single electron transfer via ion/neutral complex in the fragmentation of protonated N,N'-dibenzylpiperazines and protonated N-benzylpiperazines

Single electron transfer (SET) via ion/neutral complex (INC) was proposed and confirmed to be the key step in the formation of N-centered odd-electron ions from fragmentation of protonated even-electron ions in the present study. Upon collisional activation, the model compounds, protonated N,N′-dibenzylpiperazine and protonated N-benzylpiperazines initially dissociated to form intermediate INCs consisting of N-benzylpiperazine (or piperazine) and benzyl cation. In these ion/neutral complexes, SET reaction and direct separation as well as other reactions were observed and characterized experimentally and theoretically. Density functional theory calculations demonstrated that the energy requirement for homolysis of the precursor ion was so large that it could not be achieved, whereas the heterolytic dissociation followed by electron transfer via INC was energetically preferred. The SET process occurred only when the radical products were more stable than the separation products. The energy barrier for SET in the compounds studied was roughly estimated by comparison with other competing reactions. When the INC contained electron donor with lower ionization energy and electron acceptor with higher electron affinity, the SET reaction was more efficient.     

Where does the electron go? Electron distribution and reactivity of peptide cation radicals formed by electron transfer in the gas phase

We report the first detailed analysis at correlated levels of ab initio theory of experimentally studied peptide cations undergoing charge reduction by collisional electron transfer and competitive dissociations by loss of H atoms, ammonia, and N-C alpha bond cleavage in the gas phase. Doubly protonated Gly-Lys, (GK + 2H) (2+), and Lys-Lys, (KK + 2H) (2+), are each calculated to exist as two major conformers in the gas phase. Electron transfer to conformers with an extended lysine chain triggers highly exothermic dissociation by loss of ammonia from the Gly residue, which occurs from the ground ( X ) electronic state of the cation radical. Loss of Lys ammonium H atoms is predicted to occur from the first excited ( A ) state of the charge-reduced ions. The X and A states are nearly degenerate and show extensive delocalization of unpaired electron density over spatially remote groups. This delocalization indicates that the captured electron cannot be assigned to reduce a particular charged group in the peptide cation and that superposition of remote local Rydberg-like orbitals plays a critical role in affecting the cation-radical reactivity. Electron attachment to ion conformers with carboxyl-solvated Lys ammonium groups results in spontaneous isomerization by proton-coupled electron transfer to the carboxyl group forming dihydroxymethyl radical intermediates. This directs the peptide dissociation toward NC alpha bond cleavage that can proceed by multiple mechanisms involving reversible proton migrations in the reactants or ion-molecule complexes. The experimentally observed formations of Lys z (+*) fragments from (GK + 2H) (2+) and Lys c (+) fragments from (KK + 2H) (2+) correlate with the product thermochemistry but are independent of charge distribution in the transition states for NC alpha bond cleavage. This emphasizes the role of ion-molecule complexes in affecting the charge distribution between backbone fragments produced upon electron transfer or capture.     

Further studies on the origins of asymmetric charge partitioning in protein homodimers

Dissociation of gas-phase protonated protein dimers into their constituent monomers can result in either symmetric or asymmetric charge partitioning. Dissociation of alpha-lactalbumin homodimers with 15+ charges results in a symmetric, but broad, distribution of protein monomers with charge states centered around 8+/7+. In contrast, dissociation of the 15+ heterodimer consisting of one molecule in the oxidized form and one in the reduced form results in highly asymmetric charge partitioning in which the reduced species carries away predominantly 11+ charges, and the oxidized molecule carries away 4+ charges. This result cannot be adequately explained by differential charging occurring either in solution or in the electrospray process, but appears to be best explained by the reduced species unfolding upon activation in the gas phase with subsequent separation and proton transfer to the unfolding species in the dissociation complex to minimize Coulomb repulsion. For dimers of cytochrome c formed directly from solution, the 17+ charge state undergoes symmetric charge partitioning whereas dissociation of the 13+ is asymmetric. Reduction of the charge state of dimers with 17+ charges to 13+ via gas-phase proton transfer and subsequent dissociation of the mass selected 13+ ions results in a symmetric charge partitioning. This result clearly shows that the structure of the dimer ions with 13+ charges depends on the method of ion formation and that the structural difference is responsible for the symmetric versus asymmetric charge partitioning observed. This indicates that the asymmetry observed when these ions are formed directly from solution must come about due either to differences in the monomer conformations in the dimer that exist in solution or that occur during the electrospray ionization process. These results provide additional evidence for the origin of charge asymmetry that occurs in the dissociation of multiply charged protein complexes and indicate that some solution-phase information can be obtained from these gas-phase dissociation experiments.     

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

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. Copyright © 2015 John Wiley & Sons, Ltd.     

Guest-to-host proton transfer in melatonin-beta-cyclodextrin inclusion complex by ionspray, fast atom bombardment and tandem mass spectrometry.

Ionspray (IS) and fast atom bombardment (FAB) positive ionization mass spectrometry (MS) of 1 : 1 beta-cyclodextrin (beta-CD)-melatonin (MLT) host-guest complex allowed the detection of gaseous protonated 1 : 1 beta-CD-MLT. Tandem MS collision-induced dissociation (CID) of such protonated 1 : 1 beta-CD-MLT species showed the proton (charge) to be retained to a significant extent by the host and by its cage fragmentation products, in spite of the higher proton affinity of MLT with respect to that of beta-CD. This requires an endothermic guest-to-host proton transfer to occur within the gaseous association. Collisional activation could be accounted for by the promotion of such an endothermic process; however, the proton affinity decrease of the guest determined by the loss of the elements of acetamide, which is a dominant MS dissociation reaction of pure protonated MLT, could also provide a rationale for such an endothermic guest-to-host proton transfer. This proposal parallels the reaction scheme we had previously formulated for the analogous MS and tandem MS behaviour of 1 : 1 beta-CD-5-methoxytryptamine inclusion complex with the protonated 5-methoxytryptamine guest undergoing deamination.     

The arginine anomaly: arginine radicals are poor hydrogen atom donors in electron transfer induced dissociations

Arginine amide radicals are generated by femtosecond electron transfer to protonated arginine amide cations in the gas phase. A fraction of the arginine radicals formed (2-amino-5-dihydroguanid-1'-yl-pentanamide, 1H) is stable on the 6.7 micros time scale and is detected after collisional reionization. The main dissociation of 1H is loss of a guanidine molecule from the side chain followed by consecutive dissociations of the 2-aminopentanamid-5-yl radical intermediate. Intramolecular hydrogen atom transfer from the guanidinium group onto the amide group is not observed. These results are explained by ab initio and density functional theory calculations of dissociation and transition state energies. Loss of guanidine from 1H is calculated to require a transition state energy of 68 kJ mol(-)(1), which is substantially lower than that for hydrogen atom migration from the guanidine group. The loss of guanidine competes with the reverse migration of the arginine alpha-hydrogen atom onto the guanidyl radical. RRKM calculations of dissociation kinetics predict the loss of guanidine to account for >95% of 1H dissociations. The anomalous behavior of protonated arginine amide upon electron transfer provides an insight into electron capture and transfer dissociations of peptide cations containing arginine residues as charge carriers. The absence of efficient hydrogen atom transfer from charge-reduced arginine onto sterically proximate amide group blocks one of the current mechanisms for electron capture dissociation. Conversely, charge-reduced guanidine groups in arginine residues may function as radical traps and induce side-chain dissociations. In light of the current findings, backbone dissociations in arginine-containing peptides are predicted to involve excited electronic states and proceed by the amide superbase mechanism that involves electron capture in an amide pi* orbital, which is stabilized by through-space coulomb interaction with the remote charge carriers.     

Gas-phase ion/ion reactions of multiply protonated polypeptides with metal containing anions

Gas-phase reactions of multiply protonated polypeptides and metal containing anions represent a new methodology for manipulating the cationizing agent composition of polypeptides. This approach affords greater flexibility in forming metal containing ions than commonly used methods, such as electrospray ionization of a metal salt/peptide mixture and matrix-assisted laser desorption. Here, the effects of properties of the polypeptide and anionic reactant on the nature of the reaction products are investigated. For a given metal, the identity of the ligand in the metal containing anion is the dominant factor in determining product distributions. For a given polypeptide ion, the difference between the metal ion affinity and the proton affinity of the negatively charged ligand in the anionic reactant is of predictive value in anticipating the relative contributions of proton transfer and metal ion transfer. Furthermore, the binding strength of the ligand anion to charge sites in the polypeptide correlates with the extent of observed cluster ion formation. Polypeptide composition, sequence, and charge state can also play a notable role in determining the distribution of products. In addition to their usefulness in gas-phase ion synthesis strategies, the reactions of protonated polypeptides and metal containing anions represent an example of a gas-phase ion/ion reaction that is sensitive to polypeptide structure. These observations are noteworthy in that they allude to the possibility of obtaining information, without requiring fragmentation of the peptide backbone, about ion structure as well as the relative ion affinities associated with the reactants.     

Formation of peptide radical ions through dissociative electron transfer in ternary metal-ligand-peptide complexes

The formation and fragmentation of odd-electron ions of peptides and proteins is of interest to applications in biological mass spectrometry. Gas-phase redox chemistry occurring during collision-induced dissociation of ternary metal-ligand-peptide complexes enables the formation of a variety of peptide radicals, including the canonical radical cations, M(+?), radical dications, [M+H](2+?), radical anions, [M-2H](-?) and phosphorylated radical cations. In addition, odd-electron peptide ions with well-defined initial location of the radical site are produced through side-chain losses from the radical ions. Subsequent fragmentation of these species provides information regarding the role of charge and location of the radical site on the competition between radical-induced and proton-driven fragmentation of odd-electron peptide ions. This account summarizes current understanding of the factors that control the efficiency of the intramolecular electron transfer (ET) in ternary metal-ligand-peptide complexes resulting in formation of odd-electron peptide ions. Specifically, we discuss the effect of the metal center, the ligand and the peptide structure on the competition between the ET, proton transfer (PT) and loss of neutral peptide and neutral peptide fragments from the complex. Fundamental studies of the structures, stabilities and the energetics and dynamics of fragmentation of these complexes are also important for detailed molecular-level understanding of photosynthesis and respiration in biological systems.     

Concomitant hydride and proton transfer: an essay on competing and consecutive key reactions occurring in gaseousion/neutral complexes

The interplay of proton transfer and hydride transfer reactions in alkylbenzenium ions and related protonated di- and oligophenylalkanes is presented and discussed. While intra- and interannular proton exchange has been recognised to be an ubiquitous feature in protonated arenes, hydride abstraction is much less obvious but can become a dominating fragmentation channel in metastable ions of tert-butyl-substituted alkylbenzenium ions and related carbocations. In such cases, proton-induced release of the tert-butyl cation gives rise to ion/neutral complexes as reactive intermediates, for example, [(CH(3))(3)C(+)...arylCH(2)(α)(CH(2))(n)CH(2)(ω)aryl '] with n ≥ 0, and highly regioselective intra-complex hydride transfer occurs from all of the benzylic methylene hydride ion donor groups (α-CH(2) and ω-CH(2)) to the tert-butyl cation acting as a Lewis acid. Substituent effects on the individual contributions to the overall hydride transfer from different donor sites, including ortho-methyl groups, in particular, and the concomitant intra- complex proton transfer from the tert-butyl cation to the neutral diarylalkane constituent corroborate the view of "bisolvated" complexes as the central intermediates, in which the carbenium ion is coordinated to both of the aromatic π-electron systems. The role of cyclisation processes converting the benzylic, [M - H](+) type, ions into the isomeric benzenium, [M + H](+)-type, ions prior to fragmentation is demonstrated for several cases. This overall scenario, consisting of consecutive and/or competing intra-complex hydride abstraction and proton transfer, intraannular proton shifts (H+ ring walk) and interannular proton transfer, hydrogen exchange ("scrambling") processes, and cyclisation and other electrophilic substitution reactions, is of general importance in this field of gas-phase ion chemistry, and more recent examples concerning protonated ethers, benzylpyridinium and benzylammmonium ions are discussed in which these recurring features play central and concerted mechanistic roles as well.