Towards understanding the formation of internal fragments generated by collisionally activated dissociation for top-down mass spectrometry

Wei, Benqian; Zenaidee, Muhammad A.; Lantz, Carter; Ogorzalek Loo, Rachel R.; Loo, Joseph A.

doi:10.1016/j.aca.2021.339400

Towards understanding the formation of internal fragments generated by collisionally activated dissociation for top-down mass spectrometry

Journal Article · Wed Dec 29 23:00:00 EST 2021 · Analytica Chimica Acta

DOI:https://doi.org/10.1016/j.aca.2021.339400· OSTI ID:1976775

^[1]; ^[2]; Lantz, Carter ^[3]; ^[3]; ^[3]

University of California, Los Angeles, CA (United States); OSTI
University of California, Los Angeles, CA (United States); Macquarie University, NSW (Australia)
University of California, Los Angeles, CA (United States)

Top-down mass spectrometry (TD-MS) generates fragment ions that returns information on the polypeptide amino acid sequence. In addition to terminal fragments, internal fragments that result from multiple cleavage events can also be formed. Traditionally, internal fragments are largely ignored due to a lack of available software to reliably assign them, mainly caused by a poor understanding of their formation mechanism. To accurately assign internal fragments, their formation process needs to be better understood. Here we applied a statistical method to compare fragmentation patterns of internal and terminal fragments of peptides and proteins generated by collisionally activated dissociation (CAD). Internal fragments share similar fragmentation propensities with terminal fragments (e.g., enhanced cleavages N-terminal to proline and C-terminal to acidic residues), suggesting that their formation follows conventional CAD pathways. Internal fragments should be generated by subsequent cleavages of terminal fragments and their formation can be explained by the well-known mobile proton model. Additionally, internal fragments can be coupled with terminal fragments to form complementary product ions that span the entire protein sequence. These enhance our understanding of internal fragment formation and can help improve sequencing algorithms to accurately assign internal fragments, which will ultimately lead to more efficient and comprehensive TD-MS analysis of proteins and proteoforms.

View Accepted Manuscript (DOE)

Research Organization:: University of California, Los Angeles, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); National Science Foundation (NSF); Ruth L. Kirschstein National Research Service Award

Grant/Contract Number:: FC02-02ER63421

OSTI ID:: 1976775

Journal Information:: Analytica Chimica Acta, Journal Name: Analytica Chimica Acta Journal Issue: C Vol. 1194; ISSN 0003-2670

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

References (54)

Probing Proline Effect in CID of Protonated Peptides Vaisar, T.; Urban, J. Journal of Mass Spectrometry, Vol. 31, Issue 10 https://doi.org/10.1002/(SICI)1096-9888(199610)31:10<1185::AID-JMS396>3.0.CO;2-Q	journal	October 1996
Mobile and localized protons: a framework for understanding peptide dissociation Wysocki, Vicki H.; Tsaprailis, George; Smith, Lori L. Journal of Mass Spectrometry, Vol. 35, Issue 12 https://doi.org/10.1002/1096-9888(200012)35:12<1399::AID-JMS86>3.0.CO;2-R	journal	December 2000
Top‐down mass spectrometry of intact phosphorylated β‐casein: Correlation between the precursor charge state and internal fragments Chen, Jianzhong; Shiyanov, Pavel; Green, Kari B. Journal of Mass Spectrometry, Vol. 54, Issue 6 https://doi.org/10.1002/jms.4364	journal	May 2019
Ion activation methods for tandem mass spectrometry Sleno, Lekha; Volmer, Dietrich A. Journal of Mass Spectrometry, Vol. 39, Issue 10 https://doi.org/10.1002/jms.703	journal	January 2004
Distinguishing N- and C-terminus ions for mass spectrometry sequencing of proteins without prior degradation Aaserud, David J.; Little, Daniel P.; O'Connor, Peter B. Rapid Communications in Mass Spectrometry, Vol. 9, Issue 10 https://doi.org/10.1002/rcm.1290091002	journal	January 1995
Towards Understanding the Tandem Mass Spectra of Protonated Oligopeptides. 2: The Proline Effect in Collision-Induced Dissociation of Protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp) Bleiholder, Christian; Suhai, Sándor; Harrison, Alex G. Journal of The American Society for Mass Spectrometry, Vol. 22, Issue 6 https://doi.org/10.1007/s13361-011-0092-1	journal	April 2011
Analyzing Internal Fragmentation of Electrosprayed Ubiquitin Ions During Beam-Type Collisional Dissociation Durbin, Kenneth R.; Skinner, Owen S.; Fellers, Ryan T. Journal of The American Society for Mass Spectrometry, Vol. 26, Issue 5 https://doi.org/10.1007/s13361-015-1078-1	journal	February 2015
Defining Gas-Phase Fragmentation Propensities of Intact Proteins During Native Top-Down Mass Spectrometry Haverland, Nicole A.; Skinner, Owen S.; Fellers, Ryan T. Journal of The American Society for Mass Spectrometry, Vol. 28, Issue 6 https://doi.org/10.1007/s13361-017-1635-x	journal	April 2017
The Ups and Downs of Repeated Cleavage and Internal Fragment Production in Top-Down Proteomics Lyon, Yana A.; Riggs, Dylan; Fornelli, Luca Journal of The American Society for Mass Spectrometry, Vol. 29, Issue 1 https://doi.org/10.1007/s13361-017-1823-8	journal	October 2017
Top or Middle? Up or Down? Toward a Standard Lexicon for Protein Top-Down and Allied Mass Spectrometry Approaches Lermyte, Frederik; Tsybin, Yury O.; O’Connor, Peter B. Journal of The American Society for Mass Spectrometry, Vol. 30, Issue 7 https://doi.org/10.1007/s13361-019-02201-x	journal	May 2019
Sequential mass spectrometry applied to the study of the formation of “internal” fragment ions of protonated peptides Ballard, Kevin D.; Gaskell, Simon J. International Journal of Mass Spectrometry and Ion Processes, Vol. 111 https://doi.org/10.1016/0168-1176(91)85054-P	journal	December 1991
Principles of collisional activation in analytical mass spectrometry McLuckey, Scott A. Journal of the American Society for Mass Spectrometry, Vol. 3, Issue 6 https://doi.org/10.1016/1044-0305(92)85001-Z	journal	September 1992
Fragmentation of protonated oligopeptides XLDVLQ (X=L, H, K or R) by surface induced dissociation: additional evidence for the ‘mobile proton’ model Gu, Chungang; Somogyi, Árpád; Wysocki, Vicki H. Analytica Chimica Acta, Vol. 397, Issue 1-3 https://doi.org/10.1016/S0003-2670(99)00409-2	journal	October 1999
Fragmentation efficiencies of peptide ions following low energy collisional activation Summerfield, Scott G.; Gaskell, Simon J. International Journal of Mass Spectrometry and Ion Processes, Vol. 165-166 https://doi.org/10.1016/S0168-1176(97)00183-3	journal	November 1997
The influence of histidine on cleavage C-terminal to acidic residues in doubly protonated tryptic peptides Huang, Yingying; Wysocki, Vicki H.; Tabb, David L. International Journal of Mass Spectrometry, Vol. 219, Issue 1 https://doi.org/10.1016/S1387-3806(02)00660-7	journal	August 2002
Refining the model for selective cleavage at acidic residues in arginine-containing protonated peptides Tsaprailis, George; Somogyi, Árpád; Nikolaev, Eugene N. International Journal of Mass Spectrometry, Vol. 195-196 https://doi.org/10.1016/S1387-3806(99)00221-3	journal	January 2000
Top Down proteomics: Facts and perspectives Catherman, Adam D.; Skinner, Owen S.; Kelleher, Neil L. Biochemical and Biophysical Research Communications, Vol. 445, Issue 4 https://doi.org/10.1016/j.bbrc.2014.02.041	journal	March 2014
Is it biologically relevant to measure the structures of small peptides in the gas-phase? Barran, Perdita E.; Polfer, Nick C.; Campopiano, Dominic J. International Journal of Mass Spectrometry, Vol. 240, Issue 3 https://doi.org/10.1016/j.ijms.2004.09.013	journal	February 2005
Structural characterization of intact proteins is enhanced by prevalent fragmentation pathways rarely observed for peptides Cobb, Jennifer S.; Easterling, Michael L.; Agar, Jeffrey N. Journal of the American Society for Mass Spectrometry, Vol. 21, Issue 6 https://doi.org/10.1016/j.jasms.2010.02.009	journal	June 2010
Tandem mass spectrometry of very large molecules. 2. Dissociation of multiply charged proline-containing proteins from electrospray ionization Loo, Joseph A.; Edmonds, Charles G.; Smith, Richard D. Analytical Chemistry, Vol. 65, Issue 4 https://doi.org/10.1021/ac00052a020	journal	February 1993
Selective Gas-Phase Cleavage at the Peptide Bond C-Terminal to Aspartic Acid in Fixed-Charge Derivatives of Asp-Containing Peptides Gu, Chungang; Tsaprailis, George; Breci, Linda Analytical Chemistry, Vol. 72, Issue 23 https://doi.org/10.1021/ac000555c	journal	December 2000
Fragmentation reactions of multiply-protonated peptides and implications for sequencing by tandem mass spectrometry with low-energy collision-induced dissociation Tang, Xue Jun.; Thibault, Pierre.; Boyd, Robert K. Analytical Chemistry, Vol. 65, Issue 20 https://doi.org/10.1021/ac00068a020	journal	October 1993
Statistical Characterization of Ion Trap Tandem Mass Spectra from Doubly Charged Tryptic Peptides Tabb, David L.; Smith, Lori L.; Breci, Linda A. Analytical Chemistry, Vol. 75, Issue 5 https://doi.org/10.1021/ac026122m	journal	January 2003
Cleavage N-Terminal to Proline: Analysis of a Database of Peptide Tandem Mass Spectra Breci, Linda A.; Tabb, David L.; Yates, John R. Analytical Chemistry, Vol. 75, Issue 9 https://doi.org/10.1021/ac026359i	journal	May 2003
A Mechanistic Investigation of the Enhanced Cleavage at Histidine in the Gas-Phase Dissociation of Protonated Peptides Tsaprailis, George; Nair, Hari; Zhong, Wenqing Analytical Chemistry, Vol. 76, Issue 7 https://doi.org/10.1021/ac034971j	journal	March 2004
Influence of Basic Residue Content on Fragment Ion Peak Intensities in Low-Energy Collision-Induced Dissociation Spectra of Peptides Tabb, David L.; Huang, Yingying; Wysocki, Vicki H. Analytical Chemistry, Vol. 76, Issue 5 https://doi.org/10.1021/ac0351163	journal	March 2004
Statistical Characterization of the Charge State and Residue Dependence of Low-Energy CID Peptide Dissociation Patterns Huang, Yingying; Triscari, Joseph M.; Tseng, George C. Analytical Chemistry, Vol. 77, Issue 18 https://doi.org/10.1021/ac0480949	journal	August 2005
mMass 3: A Cross-Platform Software Environment for Precise Analysis of Mass Spectrometric Data Strohalm, Martin; Kavan, Daniel; Novák, Petr Analytical Chemistry, Vol. 82, Issue 11 https://doi.org/10.1021/ac100818g	journal	June 2010
Ion Mobility-Mass Spectrometry (IM-MS) for Top-Down Proteomics: Increased Dynamic Range Affords Increased Sequence Coverage Zinnel, Nathanael F.; Pai, Pei-Jing; Russell, David H. Analytical Chemistry, Vol. 84, Issue 7 https://doi.org/10.1021/ac300193s	journal	March 2012
Native Top-Down Electrospray Ionization-Mass Spectrometry of 158 kDa Protein Complex by High-Resolution Fourier Transform Ion Cyclotron Resonance Mass Spectrometry Li, Huilin; Wolff, Jeremy J.; Van Orden, Steve L. Analytical Chemistry, Vol. 86, Issue 1 https://doi.org/10.1021/ac4033214	journal	December 2013
Mass Spectrometric Sequencing of Proteins from Silver-Stained Polyacrylamide Gels Shevchenko, Andrej; Wilm, Matthias; Vorm, Ole Analytical Chemistry, Vol. 68, Issue 5 https://doi.org/10.1021/ac950914h	journal	January 1996
Electron Capture Dissociation for Structural Characterization of Multiply Charged Protein Cations Zubarev, Roman A.; Horn, David M.; Fridriksson, Einar K. Analytical Chemistry, Vol. 72, Issue 3 https://doi.org/10.1021/ac990811p	journal	February 2000
Increasing Top-Down Mass Spectrometry Sequence Coverage by an Order of Magnitude through Optimized Internal Fragment Generation and Assignment Schmitt, Nicholas D.; Berger, Joshua M.; Conway, Jeremy B. Analytical Chemistry, Vol. 93, Issue 16 https://doi.org/10.1021/acs.analchem.0c04670	journal	April 2021
Ion Activation Methods for Peptides and Proteins Brodbelt, Jennifer S. Analytical Chemistry, Vol. 88, Issue 1 https://doi.org/10.1021/acs.analchem.5b04563	journal	December 2015
Structural Characterization of Native Proteins and Protein Complexes by Electron Ionization Dissociation-Mass Spectrometry Li, Huilin; Sheng, Yuewei; McGee, William Analytical Chemistry, Vol. 89, Issue 5 https://doi.org/10.1021/acs.analchem.6b02377	journal	February 2017
Ion Activation Methods for Peptides and Proteins Macias, Luis A.; Santos, Inês C.; Brodbelt, Jennifer S. Analytical Chemistry, Vol. 92, Issue 1 https://doi.org/10.1021/acs.analchem.9b04859	journal	October 2019
ClipsMS: An Algorithm for Analyzing Internal Fragments Resulting from Top-Down Mass Spectrometry Lantz, Carter; Zenaidee, Muhammad A.; Wei, Benqian Journal of Proteome Research, Vol. 20, Issue 4 https://doi.org/10.1021/acs.jproteome.0c00952	journal	March 2021
Electron Ionization Dissociation of Singly and Multiply Charged Peptides Fung, Y. M. Eva; Adams, Christopher M.; Zubarev, Roman A. Journal of the American Chemical Society, Vol. 131, Issue 29 https://doi.org/10.1021/ja8087407	journal	July 2009
Influence of Peptide Composition, Gas-Phase Basicity, and Chemical Modification on Fragmentation Efficiency: Evidence for the Mobile Proton Model Dongré, Ashok R.; Jones, Jennifer L.; Somogyi, Árpád Journal of the American Chemical Society, Vol. 118, Issue 35 https://doi.org/10.1021/ja9542193	journal	January 1996
Electron Capture Dissociation of Multiply Charged Protein Cations. A Nonergodic Process Zubarev, Roman A.; Kelleher, Neil L.; McLafferty, Fred W. Journal of the American Chemical Society, Vol. 120, Issue 13 https://doi.org/10.1021/ja973478k	journal	April 1998
Top Down versus Bottom Up Protein Characterization by Tandem High-Resolution Mass Spectrometry Kelleher, Neil L.; Lin, Hong Y.; Valaskovic, Gary A. Journal of the American Chemical Society, Vol. 121, Issue 4 https://doi.org/10.1021/ja973655h	journal	February 1999
Influence of Secondary Structure on the Fragmentation of Protonated Peptides Tsaprailis, George; Nair, Hari; Somogyi, Árpád Journal of the American Chemical Society, Vol. 121, Issue 22 https://doi.org/10.1021/ja982980h	journal	June 1999
Internal Fragments Generated by Electron Ionization Dissociation Enhance Protein Top-Down Mass Spectrometry Zenaidee, Muhammad A.; Lantz, Carter; Perkins, Taylor Journal of the American Society for Mass Spectrometry, Vol. 31, Issue 9 https://doi.org/10.1021/jasms.0c00160	journal	August 2020
Internal Fragments Generated from Different Top-Down Mass Spectrometry Fragmentation Methods Extend Protein Sequence Coverage Zenaidee, Muhammad A.; Wei, Benqian; Lantz, Carter Journal of the American Society for Mass Spectrometry, Vol. 32, Issue 7 https://doi.org/10.1021/jasms.1c00113	journal	June 2021
A Data-Mining Scheme for Identifying Peptide Structural Motifs Responsible for Different MS/MS Fragmentation Intensity Patterns Huang, Yingying; Tseng, George C.; Yuan, Shinsheng Journal of Proteome Research, Vol. 7, Issue 1 https://doi.org/10.1021/pr070106u	journal	January 2008
A Systematic Investigation into the Nature of Tryptic HCD Spectra Michalski, Annette; Neuhauser, Nadin; Cox, Jürgen Journal of Proteome Research, Vol. 11, Issue 11 https://doi.org/10.1021/pr3007045	journal	October 2012
An integrated native mass spectrometry and top-down proteomics method that connects sequence to structure and function of macromolecular complexes Li, Huilin; Nguyen, Hong Hanh; Ogorzalek Loo, Rachel R. Nature Chemistry, Vol. 10, Issue 2 https://doi.org/10.1038/nchem.2908	journal	January 2018
Mass spectrometry–based proteomics turns quantitative Ong, Shao-En; Mann, Matthias Nature Chemical Biology, Vol. 1, Issue 5 https://doi.org/10.1038/nchembio736	journal	September 2005
Photodissociation mass spectrometry: new tools for characterization of biological molecules Brodbelt, Jennifer S. Chem. Soc. Rev., Vol. 43, Issue 8 https://doi.org/10.1039/C3CS60444F	journal	January 2014
Peptide and protein sequence analysis by electron transfer dissociation mass spectrometry Syka, J. E. P.; Coon, J. J.; Schroeder, M. J. Proceedings of the National Academy of Sciences, Vol. 101, Issue 26 https://doi.org/10.1073/pnas.0402700101	journal	June 2004
Protein sequencing by tandem mass spectrometry. Hunt, D. F.; Yates, J. R.; Shabanowitz, J. Proceedings of the National Academy of Sciences, Vol. 83, Issue 17 https://doi.org/10.1073/pnas.83.17.6233	journal	September 1986
Improving Protein Identification Using Complementary Fragmentation Techniques in Fourier Transform Mass Spectrometry Nielsen, Michael L.; Savitski, Mikhail M.; Zubarev, Roman A. Molecular & Cellular Proteomics, Vol. 4, Issue 6 https://doi.org/10.1074/mcp.T400022-MCP200	journal	June 2005
Primary sequence information from intact proteins by electrospray ionization tandem mass spectrometry Loo, J.; Edmonds, C.; Smith, R. Science, Vol. 248, Issue 4952 https://doi.org/10.1126/science.2326633	journal	April 1990
Progress in Top-Down Proteomics and the Analysis of Proteoforms Toby, Timothy K.; Fornelli, Luca; Kelleher, Neil L. Annual Review of Analytical Chemistry, Vol. 9, Issue 1 https://doi.org/10.1146/annurev-anchem-071015-041550	journal	June 2016

Similar Records

Top-down mass spectrometry and assigning internal fragments for determining disulfide bond positions in proteins

Journal Article · Sun Nov 13 23:00:00 EST 2022 · Analyst · OSTI ID:2418844

Internal Fragments Generated by Electron Ionization Dissociation Enhance Protein Top-Down Mass Spectrometry

Journal Article · Mon Aug 03 00:00:00 EDT 2020 · Journal of the American Society for Mass Spectrometry · OSTI ID:1799612

Exploring the fragmentation efficiency of proteins analyzed by MALDI-TOF-TOF tandem mass spectrometry using computational and statistical analyses

Journal Article · Fri May 03 00:00:00 EDT 2024 · PLoS ONE · OSTI ID:2469778

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
CAD
TD-MS
collisionally activated dissociation
fragmentation propensity
internal fragment
mobile proton model
top-down mass spectrometry

Towards understanding the formation of internal fragments generated by collisionally activated dissociation for top-down mass spectrometry

Citation Formats

References (54)

Similar Records

Related Subjects