Abstract
The MSn spectra of the [M + H]+ and b 5 peaks derived from the peptides HAAAAA, AHAAAA, AAHAAA, AAAHAA, and AAAAHA have been measured, as have the spectra of the b 4 ions derived from the first four peptides. The MS2 spectra of the [M + H]+ ions show a substantial series of bn ions with enhanced cleavage at the amide bond C-terminal to His and substantial cleavage at the amide bond N-terminal to His (when there are at least two residues N-terminal to the His residue). There is compelling experimental and theoretical evidence for formation of nondirect sequence ions via cyclization/reopening chemistry in the CID spectra of the b tons when the His residue is near the C-terminus. The experimental evidence is less clear for ions when the His residue is near the N-terminus, although this may be due to the use of multiple alanine residues in the peptide making identifying scrambled peaks more difficult. The product ion mass spectra of the b 4 and b 5 ions from these isomeric peptides with cyclically permuted amino acid sequences are similar, but also show clear differences. This indicates less active cyclization/reopening followed by fragmentation of common structures for b n ions containing His than for sequences of solely aliphatic residues. Despite more energetically favorable cyclization barriers for the b 5 structures, the b 4 ions experimental data show more clear evidence of cyclization and sequence scrambling before fragmentation. For both b 4 and b 5 the energetically most favored structure is a macrocyclic isomer protonated at the His side chain.
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Larsen, M. R.; Roepstorff, P. Mass Spectrometric Identification of Proteins and Characterization of their Post-Translational Modifications. Fresenius J. Anal. Chem. 2000, 366, 677–690.
Aebersold, R.; Goodlett, D. R. Mass Spectrometry in Proteomics. Chem. Rev. 2001, 101, 269–295.
Medzihradszky, K. Peptide Sequence Analysis. Methods Enzymol. 2005, 402, 209–244.
Paizs, B.; Suhai, S. Fragmentation Pathways of Protonated Peptides. Mass Spectrom. Rev. 2005, 24, 508–548.
Roepstorff, P.; Fohlmann, J. Proposals for a Common Nomenclature for Sequence Ions in Mass Spectra of Peptides. Biomed. Mass Spectrom. 1984, 11, 601.
Biemann, K. Contributions of Mass Spectrometry to Peptide and Protein Structure. Biomed. Env. Mass Spectrom. 1988, 16, 99–111.
Harrison, A. G.; Young, A. B.; Bleiholder, C.; Suhai, S.; Paizs, B. Scrambling of Sequence Information in Collision-Induced Dissociation of Peptides. J. Am. Chem. Soc. 2006, 128, 10364–10365.
Bleiholder, C.; Osburn, S.; Williams, T. D.; Suhai, S.; Van Stipdonk, M.; Harrison, A. G.; Paizs, B. Sequence-Scrambling Pathways of Protonated Peptides. J. Am. Chem. Soc. 2008, 130, 17774–17789.
Mueller, D. R.; Eckersley, M.; Richter, W. Hydrogen Transfer Reactions in the Formation of “Y + 2” Sequence Ions from Protonated Peptides. Org. Mass Spectrom. 1988, 23, 217–222.
Cordero, M. M.; Houser, J. J.; Wesdemiotis, C. The Neutral Products Formed During Backbone Cleavage of Protonated Peptides in Tandem Mass Spectrometry. Anal. Chem. 1993, 65, 1594–1601.
Harrison, A. G. To b or not to b. The Ongoing Saga of Peptide b Ions. Mass Spectrom. Rev. 2009, 18, 640–654.
Yalcin, T.; Khouw, C.; Csizmadia, I. G.; Peterson, M. R.; Harrison, A. G. Why are b Ions Stable Species in Peptide Mass Spectra? J. Am. Soc. Mass Spectrom. 1995, 6, 1165–1174.
Yalcin, T.; Csizmadia, I. G.; Peterson, M. R.; Harrison, A. G. The Structures and Fragmentation of Bn (n ≥ 3) Ions in Peptide Mass Spectra. J. Am. Soc. Mass Spectrom. 1996, 7, 233–242.
Mold, M. J.; Wesdemiotis, C.; Yalcin, T.; Harrison, A. G. Amide Bond Dissociation in Protonated Peptides. Structures of the N-terminal Ionic and Neutral Fragments. Int. J. Mass Spectrom. Ion Processes 1997, 164, 137–153.
Paizs, B.; Lendvay, G.; Vékey, K.; Suhai, S. Formation of b +2 Ions from Protonated Peptides. Rapid Commun. Mass Spectrom. 1999, 13, 523–533.
Harrison, A. G.; Csizmadia, I. G.; Tang, T.-H. Structures and Fragmentation of b2 Ions in Peptide Mass Spectra. J. Am. Soc. Mass Spectrom. 2000, 11, 427–436.
Rodriquez, C. F.; Shoeib, T.; Chu, I. K.; Siu, K. W. M.; Hopkinson, A. C. Comparison Between Protonation, Lithiation and Argentination of 5-Oxazolones. A Study of a Key Intermediate in Gas-Phase Peptide Sequencing. J. Phys. Chem. A 2000, 104, 5335–5342.
Polfer, N. C.; Oomens, J.; Suhai, S.; Paizs, B. Spectroscopic and Theoretical Evidence for Oxazolone Ring Formation in Collision-Induced Dissociation of Peptides. J. Am. Chem. Soc. 2005, 127, 17154–17155.
Polfer, N. C.; Oomens, J.; Suhai, S.; Paizs, B. Infrared Spectroscopy and Theoretical Studies on Gas-Phase Protonated Leu-Enkephalin and Its Fragments: Direct Experimental Evidence for the Mobile Proton. J. Am. Chem. Soc. 2007, 129, 5887–5897.
Yoon, S. H.; Chamot-Rooke, J.; Perkins, B. R.; Hilderbrand, A. E.; Poutsma, I. C.; Wysocki, V. H. IRMPD. Spectroscopy Shows That AGG Forms an Oxazolone b2 Ion. J. Am. Chem. Soc. 2008, 130, 17644–17645.
Oomens, J.; Young, S.; Molesworth, S.; Van Stipdonk, M. Spectroscopic Evidence for an Oxazolone Structure of the b2 Ion from Protonated Tri-Alanine. J. Am. Soc. Mass Spectrom. 2009, 20, 334–339.
Bythell, B. J.; Erlekam, U.; Paizs, B.; Maitre, P. Infrared Spectroscopy of Fragments Derived from Tryptic Peptides. Chem. Phys. Chem. 2009, 10, 883–885.
Bythell, B. I.; Somogyi,,Á.; Paizs, B. What is the Structure of b2 Ions Generated from Doubly Protonated Tryptic Peptides? J. Am. Soc. Mass Spectrom. 2009, 10, 618–624.
Yalcin, T.; Harrison, A. G. Ion Chemistry of Protonated Lysine Derivatives. J. Mass Spectrom. 1996, 31, 1237–1243.
Tu, Y.-P.; Harrison, A. G. The b1 Ion Derived from Methionine is a Stable Species. Rapid Commun. Mass Spectrom. 1998, 12, 849–851.
Yu, W.; Vath, J. E.; Huberty, M. C.; Martin, S. A. Identification of the Facile Gas-phase Cleavage of the Asp-Pro and Asp-Xxx Peptide Bonds in Matrix-assisted Laser Desorption Time-of-flight Mass Spectrometry. Anal. Chem. 1993, 65, 3015–3023.
Farrugia, J. M.; Taverner, T.; O’Hair, R. A. J. Side-Chain Involvement in the Fragmentation Reactions of Protonated Methyl Esters of Histidine and its Peptides. Int. J. Mass Spectrom. 2001, 209, 99–112.
Farrugia, J. M.; O’Hair, R. A. J.; Reid, G. A. Do All b2 Ions Have Oxazolone Structures? Multistage Mass Spectrometry and Ab Initio Studies on Protonated N-Acyl Amino Acid Methyl Ester Model Systems. Int. J. Mass Spectrom. 2001, 210/211, 71–87.
Csonka, I. P.; Paizs, B.; Lendvay, G.; Suhai, S. Proton Mobility and Main Fragmentation Pathways of Protonated Lysylglycine. Rapid Commun. Mass Spectrom. 2001, 15, 1457–1472.
Knapp-Mohammady, M.; Young, A. B.; Paizs, B.; Harrison, A. G. Fragmentation of Doubly-Protonated Pro-His-Xaa Tripeptides: Formation of b 2+2 Ions. J. Am. Soc. Mass Spectrom. 2009, 10, 2135–2143.
Bythell, B. J.; Csonka, I. P.; Suhai, S.; Barofsky, D. F.; Paizs, B. Gas-Phase Structure and Fragmentation Pathways of Singly Protonated Peptides with N-Terminal Arginine J. Phys. Chem. A, unpublished (submitted).
Allen, J. M.; Racine, A. H.; Berman, A. M.; Johnson, J. S.; Bythell, B. J.; Paizs, B.; Glish, G. L. Why are a3 Ions Rarely Observed? J. Am. Soc. Mass Spectrom. 2008, 19, 1764–1770.
Erlekam, U.; Bythell, B. J.; Scuderi, D.; Van Stipdonk, M.; Paizs, B.; Maitre, P. Infrared Spectroscopy of Fragments of Protonated Peptides. Direct Evidence for Macrocyclic Structure of b 5 Ions. J. Am. Chem. Soc. 2009, 131, 11503–11508.
Tang, X.-J.; Thibault, P.; Boyd, R. K. Fragmentation of Multiply-Protonated Peptides and Implications for Sequencing by Tandem Mass Spectrometry with Low-Energy Collision-Induced Dissociation. Anal. Chem. 1993, 65, 2824–2834.
Tang, X.-J.; Boyd, R. K. Rearrangement of Doubly-Charged Acylium Ions from Lysyl and Ornithyl Peptides. Rapid Commun. Mass Spectrom. 1994, 8, 678–686.
Yague, J.; Paradela, A.; Ramos, M.; Ogueta, S.; Marina, A.; Barabona, F.; Lopez de Castro, J. A.; Vazquez, J. Peptide Rearrangement During Ion Trap Fragmentation: Added Complexity to MS/MS Spectra. Anal. Chem. 2003, 75, 1524–1535.
Mouls, L.; Aubagnac, J. L.; Enjalbal, C. Low Energy Peptide Fragmentations in an ESI-Q-TOF Type Mass Spectrometer, J. Proteome Res. 2007, 6, 1378–1391.
Harrison, A. G. Sequence Scrambling Through Cyclization of b 5 Ions. J. Am. Soc. Mass Spectrom. 2008, 19, 1776–1780.
Molesworth, S.; Osburn, S.; Van Stipdonk, M. Influence of Size on Apparent Scrambling of Sequence During CID of b-Type Ions. J. Am. Soc. Mass Spectrom. 2009, 10, 2174–2181.
Riba-Garcia, I.; Giles, K.; Bateman, R. H.; Gaskell, S. J. Evidence for Structural Variants of a- and b-Type Peptide Fragment Ions Using Combined Ion Mobility/Mass Spectrometry. J. Am. Soc. Mass Spectrom. 2008, 19, 609–613.
Harrison, A. G. Cyclization of Peptide b9 Ions. J. Am. Soc. Mass Spectrom. 2009, 10, 2248–2253.
Fattahi, A.; Zekavat, B.; Solouki, T. H/D Exchange Kinetics: Experimental Evidence for Formation of Different b Fragment Ion Conformers/ Isomers During the Gas-Phase Peptide Sequencing. J. Am. Soc. Mass Spectrom. 2010, 21, 358–369.
Paizs, B.; Suhai, S. Towards Understanding the Tandem Mass Spectra of Protonated Oligopeptides. 1: Mechanism of Amide Bond Cleavage. J. Am. Soc. Mass Spectrom. 2004, 15, 103–113.
Wyttenbach, T.; Paizs, B.; Barran, P.; Breci, L. A.; Liu, D.; Suhai, S.; Wysocki, V. H.; Bowers, M. T. The Effect of the Initial Water of Hydration on the Energetics, Structures, and H/D-exchange Mechanism of a Family of Pentapeptides: An Experimental and Theoretical Study. J. Am. Chem. Soc. 2003, 123, 13768–13775.
Case, D. A.; Pearlman, D. A.; Caldwell, J. W.; Cheatham, T. E. III; Ross, W. S.; Simmerling, C. L.; Darden, T. A.; Merz, K. M.; Stanton, R. V.; Cheng, A. L.; Vincent, J. T.; Crowley, M.; Tsui, V.; Radmer, R. J.; Duan, Y.; Pitera, J.; Massova, I. G.; Seibel, G. L.; Singh, U. C.; Weiner, P. K.; Kollmann, P. A. AMBER 99; University of California: San Francisco, 1999.
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A. Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Parkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, L.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.: Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian C2; Gaussian Inc.: Wallingford CT, 2004.
Tsaprailis, G.; Nair, H.; Zhong, W.; Kuppannan, K.; Futrell, J. H.; Wysocki, V. H. A Mechanistic Investigation of the Enhanced Cleavage at Histidine in the Gas-Phase Dissociation of protonated Peptides. Anal. Chem. 2004, 76, 2083–2094.
Paizs, B.; Suhai, S. Towards Understanding Some Ion Intensity Relationships for the Tandem Mass Spectra of Protonated Peptides. Rapid Commun. Mass Spectrom. 2002, 16, 1699–1702.
Bleiholder, C.; Suhai, S.; B. Paizs. Revising the Proton Affinity Scale of the Naturally Occurring α-Amino Acids. J. Am. Soc. Mass Spectrom. 2006, 17, 1275–1281.
Harrison, A. G.; Young, A. B. Fragmentation of Protonated Oligo-Alanines: Amide Bond Cleavage and Beyond. J. Am. Soc. Mass Spectrom. 2004, 15, 1810–1819.
Wysocki, V. H.; Tsaprailis, G.; Smith, L. L.; Breci, L. A. Commentary— Mobile and Localized Protons: A Framework for Understanding Peptide Dissociation. J. Mass Spectrom. 2000, 35, 1399–1406.
Ballard, K. D.; Gaskell, S. J. Dehydration of Peptide [M + H]+ Ions in the Gas Phase. J. Am. Soc. Mass Spectrom. 1993, 4, 477–481.
Reid, G. E.; Simpson, R. J.; O’Hair, R. A. J. Probing the Fragmentation Reactions of Protonated Glycine Oligomers Via Multistage Mass Spectrometry and Gas Phase Ion Molecule Hydrogen/Deuterium Exchange Int. J. Mass Spectrom. 1999, 190/191, 209–230.
Bythell, B. J.; Dain, R. P.; Curtice, S. S.; Oomens, J.; Steill, J. D.; Groenewold, G. S.; Paizs, B.; Van Stipdonk, M. J. Structure of [M + H − H2O]+ from Protonated Tetraglycine Revealed by Landem Mass Spectrometry and IRMPD Spectroscopy J. Phys. Chem. A 2010, 114, 5076–5082.
Cooper, T.; Talaty, E.; Grove, J.; Van Stipdonk, M.; Suhai, S.; Paizs, B. Isotope Labeling and Theoretical Study of the Formation of a3* Ions from Protonated Tetragiycine. J. Am. Soc. Mass Spectrom. 2006, 17, 1654–1664.
Harrison, A. G. Fragmentation Reactions of Some Peptide b3 Ions: An Energy-Resolved Study. Rapid Commun. Mass Spectrom. 2009, 13, 1298–1302.
Bythell, B. J.; Molesworth, S.; Osburn, S.; Cooper, T.; Paizs, B.; Van Stipdonk, M. Structure and Reactivity of an and an* Peptide Fragments Investigated Using Isotope Labeling, Tandem Mass Spectrometry and Density Functional Theory Calculations. J. Am. Soc Mass Spectrom. 2008, 19, 1788–1798.
Chen, X.; Yu, L.; Steill, J. D.; Oomens, J.; Polfer, N. C. Effect of Peptide Fragment Size on the Propensity of Cyclization in Collision-Induced Dissociation: Oligoglycine b2-bs. J. Am. Chem Soc., 2009, 131, 18272–18282.
Paizs, B.; Szlávik, Z.; Lendvay, G.; Vékey, K.; Suhai, S. Formation of a +2 Ions of Protonated Peptides. An Ab Initio Study. Rapid Commun. Muss Spectrom. 2000, 14, 746–755.
El Aribi, H.; Orlova, G.; Rodriquez, C. F.; Almeida, D. R. P.; Hopkinson, A. C.; Siu, K. W. M. Fragmentation Mechanisms of Product Ions from Protonated Tripeptides. J. Phys. Chem. B 2004, 108, 18743–18749.
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Bythell, B.J., Knapp-Mohammady, M., Paizs, B. et al. Effect of the his residue on the cyclization of b ions. J Am Soc Mass Spectrom 21, 1352–1363 (2010). https://doi.org/10.1016/j.jasms.2010.05.006
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DOI: https://doi.org/10.1016/j.jasms.2010.05.006