Gas-phase regiocontrolled generation of charged amino acid and peptide radicals

Wee, Sheena; Mortimer, Adam; Moran, Damian; Wright, Adam; Barlow, Christopher K.; O’Hair, Richard A. J.; Radom, Leo; Easton, Christopher J.

doi:10.1039/b608724h

Cited by 55 publications

(81 citation statements)

References 21 publications

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“…Side-chain losses are commonly observed in radical-mediated peptide dissociation [12][13][14][15][16][17][18][19][20][21]. Most side-chain losses can be explained by hydrogen atom abstraction followed by ␤ scission.…”

Section: Resultsmentioning

confidence: 99%

“…Other radicalbased dissociation methods have also been developed to interrogate peptides and proteins. In these experiments, specific bonds are modified either covalently, [12][13][14] or by attachment of a metal-complex, [15][16][17] such that the bond is predisposed towards homolytic cleavage. Activation of these precursor molecules by CID generates the radical species.…”

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confidence: 99%

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Tracking radical migration in large hydrogen deficient peptides with covalent labels: Facile movement does not equal indiscriminate fragmentation

Julian

2009

J. Am. Soc. Mass Spectrom.

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Photodissociation of iodo-tyrosine modified peptides yields localized radicals on the tyrosine side chain, which can be further dissociated by collisional activation. We have performed extensive experiments on model peptides, RGYALG, RGYG, and their derivatives, to elucidate the mechanisms underlying backbone fragmentation at tyrosine. Neither acetylation nor deuteration of the tyrosyl phenolic hydrogen significantly affects backbone fragmentation. However, deuterium migration from the tyrosyl ␤ carbon is concomitant with cleavage at tyrosine. Substitution of tyrosine with 4-hydroxyphenylglycine, which does not have ␤ hydrogens, results in almost complete elimination of backbone fragmentation at tyrosine. These results suggest that a radical situated on the ␤ carbon is required for a-type fragmentation in hydrogen-deficient radical peptides. Replacement of the ␣H of the residue adjacent to tyrosine with methyl groups results in significant diminution of backbone fragmentation. The initial radical abstracts an ␣H from the adjacent amino acid, which is poised to "rebound" and abstract the ␤H of tyrosine through a six-membered transition-state. Subsequent ␤-scission leads to the observed a-type backbone fragment. These results from deuterated peptides clearly reveal that radical migration in peptides can occur and that multiple migrations are not infrequent. Counterintuitively, close examination of all experimental results reveals that the probability for fragmentation at a particular residue is well correlated with thermodynamic radical stability. A-type fragmentation therefore appears to be most likely when favorable thermodynamics are combined with the relevant kinetic control. These results are consistent with ab initio calculations, which demonstrate that barriers to migration are significantly smaller in magnitude than probable dissociation thresholds. (J Am Soc

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Tracking radical migration in large hydrogen deficient peptides with covalent labels: Facile movement does not equal indiscriminate fragmentation

Julian

2009

J. Am. Soc. Mass Spectrom.

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“…With the advent of electrospray ionization, electron ionization methods, first reported by Andersson in 1958 [22] have largely been supplanted by methods involving collision induced dissociation (CID) or UV photodissociation of peptide derivatives. Examples include CID of: (1) redox active metal complexes composed of a metal in a higher oxidation state (like Fe 3+ or Cu 2+ ), peptide or amino acid of interest, and an auxiliary ligand [23][24][25][26][27][28][29][30][31]; (2) an amino acid or peptide covalently modified to include a derivative with a weak bond that is susceptible to homolytic cleavage, such as peroxycarbamate derivatives to introduce a radical on lysine [24,25] or the Nterminus of a peptide 26 and serine nitrate esters to produce carbon centered radicals [27,28]. Another method involves the UV photodissociation of iodotyrosine [29,30] or modified phosphorylated serine and threonine [31].…”

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confidence: 99%

Structure and Reactivity of theN-Acetyl-Cysteine Radical Cation and Anion: Does Radical Migration Occur?

Osburn

Berden

O’Hair

et al. 2011

J. Am. Soc. Mass Spectrom.

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The structure and reactivity of the N-acetyl-cysteine radical cation and anion were studied using ion-molecule reactions, infrared multi-photon dissociation (IRMPD) spectroscopy, and density functional theory (DFT) calculations. The radical cation was generated by first nitrosylating the thiol of N-acetyl-cysteine followed by the homolytic cleavage of the S-NO bond in the gas phase. IRMPD spectroscopy coupled with DFT calculations revealed that for the radical cation the radical migrates from its initial position on the sulfur atom to the α-carbon position, which is 2.5 kJ mol -1 lower in energy. The radical migration was confirmed by time-resolved ion-molecule reactions. These results are in contrast with our previous study on cysteine methyl ester radical cation (Osburn et al., Chem. Eur. J. 2011, 17, 873-879) and the study by Sinha et al. for cysteine radical cation (Phys. Chem. Chem. Phys. 2010, 12, 9794-9800) where the radical was found to stay on the sulfur atom as formed. A similar approach allowed us to form a hydrogen-deficient radical anion of N-acetyl-cysteine, (M -2H)•-. IRMPD studies and ion-molecule reactions performed on the radical anion showed that the radical remains on the sulfur, which is the initial and more stable (by 63.6 kJ mol -1 ) position, and does not rearrange.

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“…Numerous methods (including electron initiated fragmentation, 1,2 direct bond homolysis by photolysis 3 or collisional activation, [4][5][6][7][8][9][10] and photoionisation 11 ) can be used to generate peptide radicals. Following radical generation, the subsequent fragmentation chemistry of the peptide is typically dominated by radical-directed processes, making the location of the radical crucial as the initiation point for fragmentation.…”

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confidence: 99%

Ion–molecule reactions reveal facile radical migration in peptides

2009

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Gas-phase regiocontrolled generation of charged amino acid and peptide radicals

Abstract: The combined use of advanced mass spectrometry experiments, condensed-phase synthesis of serine and homoserine nitrate ester radical precursors, and high-level ab initio calculations provides a powerful way of examining the fundamental reactivity of radicals derived from peptides.

Cited by 55 publications

References 21 publications

Tracking radical migration in large hydrogen deficient peptides with covalent labels: Facile movement does not equal indiscriminate fragmentation

Tracking radical migration in large hydrogen deficient peptides with covalent labels: Facile movement does not equal indiscriminate fragmentation

Structure and Reactivity of theN-Acetyl-Cysteine Radical Cation and Anion: Does Radical Migration Occur?

Ion–molecule reactions reveal facile radical migration in peptides

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