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Enhanced Multiplexing in Fourier Transform Charge Detection Mass Spectrometry by Decoupling Ion Frequency from Mass to Charge Ratio

  • Conner C. Harper
  • Evan R. WilliamsEmail author
Research Article

Abstract

Weighing single ions with charge detection mass spectrometry (CDMS) makes it possible to obtain the masses of molecules of essentially unlimited size even in highly heterogeneous samples, but producing a mass histogram that is representative of all of the components in a mixture requires substantial measurement time. Multiple ions can be trapped to reduce analysis time but ion signals can overlap. To determine the maximum gains in analysis speed possible with current instrumentation with multiple ion trapping, simulations calculating the frequency and overlap rate of ions with different mass, charge, and energy ranges were performed. For an analyte with a broad mass distribution, such as long chain polyethylene glycol (PEG, 8 MDa), gains in analysis speed of up to 160 times that of prior CDMS experiments are possible. For signals from homogeneous samples, ions with the same m/z have frequencies that overlap and interfere, reducing the effectiveness of multiplexing in experiments where ions have the same energy per charge. We show that by maximizing the decoupling of ion m/z from frequency using a broad range of ion energies, the rate of signal overlap is significantly reduced making it possible to trap more ions. Under optimum decoupling conditions, a measurement speed nearly 50 times greater than that of prior CDMS experiments is possible for RuBisCO (517 kDa). The reduction in overlap due to decoupling also results in more accurate quantitation in samples that contain multiple analytes with different concentrations.

Keywords

CDMS Charge detection mass spectrometry Multiplexing Fourier transform Megadalton Ion energy Ion frequency High-throughput Decoupling Native MS 

Notes

Acknowledgements

This material is based upon work supported by the National Science Foundation under CHE-1609866.

Supplementary material

13361_2019_2330_MOESM1_ESM.txt (3 kb)
ESM 1 (TXT 3 kb)

References

  1. 1.
    Susa, A.C., Xia, Z., Williams, E.R.: Native Mass Spectrometry from Common Buffers with Salts that Mimic the Extracellular Environment. Angew Chem Int Ed. 56, 7912–7915 (2017)CrossRefGoogle Scholar
  2. 2.
    Gavriilidou, A.F.M., Gülbakan, B., Zenobi, R.: Influence of Ammonium Acetate Concentration on Receptor–Ligand Binding Affinities Measured by Native Nano ESI-MS: A Systematic Study. Anal Chem. 87, 10378–10384 (2015)Google Scholar
  3. 3.
    Loo, J.A.: Electrospray Ionization Mass Spectrometry: A Technology for Studying Noncovalent Macromolecular Complexes. Int J Mass Spectrom. 200, 175–186 (2000)CrossRefGoogle Scholar
  4. 4.
    Wysocki, V.H., Jones, C.M., Galhena, A.S., Blackwell, A.E.: Surface-Induced Dissociation shows Potential to be More Informative than Collision-Induced Dissociation for Structural Studies of Large Systems. J Am Soc Mass Spectrom. 19, 903–913 (2008)CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Benesch, J.L.P., Aquilina, J.A., Ruotolo, B.T., Sobott, F., Robinson, C.V.: Tandem Mass Spectrometry Reveals the Quaternary Organization of Macromolecular Assemblies. Chem Biol. 13, 597–605 (2006)CrossRefPubMedGoogle Scholar
  6. 6.
    Lössl, P., Snijder, J., Heck, A.J.R.: Boundaries of Mass Resolution in Native Mass Spectrometry. J Am Soc Mass Spectrom. 25, 906–917 (2014)CrossRefPubMedGoogle Scholar
  7. 7.
    O’Connor, P.B., McLafferty, F.W.: Oligomer Characterization of 4–23 kDa Polymers by Electrospray Fourier Transform Mass Spectrometry. J Am Chem Soc. 117, 12826–12831 (1995)Google Scholar
  8. 8.
    Robb, D.B., Brown, J.M., Morris, M., Blades, M.W.: Method of Atmospheric Pressure Charge Stripping for Electrospray Ionization Mass Spectrometry and its Application for the Analysis of Large Poly(Ethylene Glycol)s. Anal Chem. 86, 9644–9652 (2014)CrossRefPubMedGoogle Scholar
  9. 9.
    McKay, A.R., Ruotolo, B.T., Ilag, L.L., Robinson, C.V.: Mass Measurements of Increased Accuracy Resolve Heterogeneous Populations of Intact Ribosomes. J Am Chem Soc. 128, 11433–11442 (2006)Google Scholar
  10. 10.
    Morgner, N., Robinson, C.V.: Massign: An Assignment Strategy for Maximizing Information from the Mass Spectra of Heterogeneous Protein Assemblies. Anal Chem. 84, 2939–2948 (2012)CrossRefPubMedGoogle Scholar
  11. 11.
    Sader, J.E., Hanay, M.S., Neumann, A.P., Roukes, M.L.: Mass Spectrometry using Nanomechanical Systems: Beyond the Point-Mass Approximation. Nano Lett. 18, 1608–1614 (2018)CrossRefPubMedGoogle Scholar
  12. 12.
    Hanay, M.S., Kelber, S., Naik, A.K., Chi, D., Hentz, S., Bullard, E.C., Colinet, E., Duraffourg, L., Roukes, M.L.: Single-Protein Nanomechanical Mass Spectrometry in Real Time. Nat Nanotechnol. 7, 602–608 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Smith, R.D., Cheng, X., Brace, J.E., Hofstadler, S.A., Anderson, G.A.: Trapping, Detection and Reaction of very Large Single Molecular Ions by Mass Spectrometry. Nature. 369, 137–139 (1994)CrossRefGoogle Scholar
  14. 14.
    Bruce, J.E., Cheng, X., Bakhtiar, R., Wu, Q., Hofstadler, S.A., Anderson, G.A., Smith, R.D.: Trapping, Detection, and Mass Measurement of Individual Ions in a Fourier Transform Ion Cyclotron Resonance Mass Spectrometer. J Am Chem Soc. 116, 7839–7847 (1994)CrossRefGoogle Scholar
  15. 15.
    Makarov, A., Denisov, E.: Dynamics of Ions of Intact Proteins in the Orbitrap Mass Analyzer. J Am Chem Soc. 20, 1486–1495 (2009)Google Scholar
  16. 16.
    Kafader, J.O., Melani, R.D., Senko, M.W., Makarov, A.A., Kelleher, N.L., Compton, P.D.: Measurement of Individual Ions Sharply Increases the Resolution of Orbitrap Mass Spectra of Proteins. Anal Chem. 91, 2776–2783 (2019)CrossRefPubMedGoogle Scholar
  17. 17.
    Wuerker, R.F., Shelton, H., Langmuir, R.V.: Electrodynamic Containment of Charged Particles. J Appl Phys. 30, 342–349 (1959)CrossRefGoogle Scholar
  18. 18.
    Philip, M.A., Gelbard, F., Arnold, S.: An Absolute Method for Aerosol Particle Mass and Charge Measurement. J Colloid Interface Sci. 91, 507–515 (1983)CrossRefGoogle Scholar
  19. 19.
    Hars, G., Tass, Z.: Application of Quadrupole Ion Trap for the Accurate Mass Determination of Submicron Size Charged Particles. J Appl Phys. 77, 4245–4250 (1995)CrossRefGoogle Scholar
  20. 20.
    Schlemmer, S., Illemann, J., Wellert, S., Gerlich, D.: Nondestructive High-Resolution and Absolute Mass Determination of Single Charged Particles in a Three-Dimensional Quadrupole Trap. J Appl Phys. 90, 5410–5418 (2001)CrossRefGoogle Scholar
  21. 21.
    Howder, C.R., Bell, D.M., Anderson, S.L.: Optically Detected, Single Nanoparticle Mass Spectrometer with Pre-Filtered Electrospray Nanoparticle Source. Rev Sci Instrum. 85, 014104 (2014)CrossRefPubMedGoogle Scholar
  22. 22.
    Twerenbold, D.: Biopolymer Mass Spectrometer with Cryogenic Particle Detectors. Nucl Inst Methods Phys Res A. 370, 253–255 (1996)CrossRefGoogle Scholar
  23. 23.
    Sipe, D.M., Plath, L.D., Aksenov, A.A., Feldman, J.S., Bier, M.E.: Characterization of Mega-Dalton-Sized Nanoparticles by Superconducting Tunnel Junction Cryodetection Mass Spectrometry. ACS Nano. 12, 2591–2602 (2018)CrossRefPubMedGoogle Scholar
  24. 24.
    Barney, B.L., Pratt, S.N., Austin, D.E.: Survivability of Bare, Individual Bacillus Subtilis Spores to High-Velocity Surface Impact: Implications for Microbial Transfer through Space. Planet Space Sci. 125, 20–26 (2016)CrossRefGoogle Scholar
  25. 25.
    Benner, W.H.: A Gated Electrostatic Ion Trap to Repetitiously Measure the Charge and M/Z of Large Electrospray Ions. Anal Chem. 69, 4162–4168 (1997)Google Scholar
  26. 26.
    Keifer, D.Z., Pierson, E.E., Jarrold, M.F.: Charge Detection Mass Spectrometry: Weighing Heavier Things. Analyst. 142, 1654–1671 (2017)CrossRefPubMedGoogle Scholar
  27. 27.
    Keifer, D.Z., Jarrold, M.F.: Single-Molecule Mass Spectrometry. Mass Spectrom Rev. 36, 715–733 (2017)CrossRefPubMedGoogle Scholar
  28. 28.
    Doussineau, T., Bao, C.Y., Antoine, R., Dugourd, P., Zhang, W., D’Agosto, F., Charleux, B.: Direct Molar Mass Determination of Self-Assembled Amphiphilic Block Copolymer Nanoobjects using Electrospray-Charge Detection Mass Spectrometry. ACS Macro Lett. 1, 414–417 (2012)CrossRefGoogle Scholar
  29. 29.
    Elliott, A.G., Merenbloom, S.I., Chakrabarty, S., Williams, E.R.: Single Particle Analyzer of Mass: A Charge Detection Mass Spectrometer with a Multi-Detector Electrostatic Ion Trap. Int J Mass Spectrom. 414, 45–55 (2017)CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Adamson, B.D., Miller, M.E.C., Continetti, R.E.: The Aerosol Impact Spectrometer: A Versatile Platform for Studying the Velocity Dependence of Nanoparticle-Surface Impact Phenomena. EPJ Tech Instrum. 4(2), (2017)Google Scholar
  31. 31.
    Lutomski, C.A., Lyktey, N.A., Pierson, E.E., Zhao, Z., Zlotnick, A., Jarrold, M.F.: Multiple Pathways in Capsid Assembly. J Am Chem Soc. 140, 5784–5790 (2018)CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Lutomski, C.A., Gordon, S.M., Remaley, A.T., Jarrold, M.F.: Resolution of Lipoprotein Subclasses by Charge Detection Mass Spectrometry. Anal Chem. 90, 6353–6356 (2018)CrossRefPubMedGoogle Scholar
  33. 33.
    Pierson, E.E., Contino, N.C., Keifer, D.Z., Jarrold, M.F.: Charge Detection Mass Spectrometry for Single Ions with an Uncertainty in the Charge Measurement of 0.65 E. J Am Soc Mass Spectrom. 26, 1213–1220 (2015)CrossRefPubMedGoogle Scholar
  34. 34.
    Pierson, E.E., Keifer, D.Z., Asokan, A., Jarrold, M.F.: Resolving Adeno-Associated Viral Particle Diversity with Charge Detection Mass Spectrometry. Anal Chem. 88, 6718–6725 (2016)CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Keifer, D.Z., Pierson, E.E., Hogan, J.A., Bedwell, G.J., Prevelige, P.E., Jarrold, M.F.: Charge Detection Mass Spectrometry of Bacteriophage P22 Procapsid Distributions Above 20 MDa. Rapid Commun Mass Spectrom. 28, 483–488 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Pierson, E.E., Keifer, D.Z., Contino, N.C., Jarrold, M.F.: Probing Higher Order Multimers of Pyruvate Kinase with Charge Detection Mass Spectrometry. Int J Mass Spectrom. 337, 50–56 (2013)CrossRefGoogle Scholar
  37. 37.
    Elliott, A.G., Harper, C.C., Lin, H., Williams, E.R.: Mass, Mobility and MSN Measurements of Single Ions using Charge Detection Mass Spectrometry. Analyst. 142, 2760–2769 (2017)CrossRefPubMedGoogle Scholar
  38. 38.
    Elliott, A.G., Harper, C.C., Lin, H., Susa, A.C., Xia, Z., Williams, E.R.: Simultaneous Measurements of Mass and Collisional Cross-Section of Single Ions with Charge Detection Mass Spectrometry. Anal Chem. 89, 7701–7708 (2017)CrossRefPubMedGoogle Scholar
  39. 39.
    Harper, C.C., Elliott, A.G., Lin, H., Williams, E.R.: Determining Energies and Cross Sections of Individual Ions using Higher-Order Harmonics in Fourier Transform Charge Detection Mass Spectrometry (FT-CDMS). J Am Soc Mass Spectrom. 29, 1861–1869 (2018)CrossRefPubMedGoogle Scholar
  40. 40.
    Keifer, D.Z., Motwani, T., Teschke, C.M., Jarrold, M.F.: Acquiring Structural Information on Virus Particles with Charge Detection Mass Spectrometry. J Am Soc Mass Spectrom. 27, 1028–1036 (2016)CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Keifer, D.Z., Shinholt, D.L., Jarrold, M.F.: Charge Detection Mass Spectrometry with almost Perfect Charge Accuracy. Anal Chem. 87, 10330–10337 (2015)Google Scholar
  42. 42.
    Hogan, J.A., Jarrold, M.F.: Optimized Electrostatic Linear Ion Trap for Charge Detection Mass Spectrometry. J Am Soc Mass Spectrom. 29, 2086–2095 (2018)CrossRefPubMedGoogle Scholar
  43. 43.
    Harper, C.C., Elliott, A.G., Oltrogge, L.M., Savage, D.F., Williams, E.R.: Multiplexed Charge Detection Mass Spectrometry for High-Throughput Single Ion Analysis of Large Molecules. Anal Chem. 91, 7458–7465 (2019).Google Scholar
  44. 44.
    Draper, B.E., Jarrold, M.F.: Real-Time Analysis and Signal Optimization for Charge Detection Mass Spectrometry. J Am Soc Mass Spectrom. 30, 898–904 (2019)CrossRefPubMedGoogle Scholar
  45. 45.
    Marshall, A.G., Hendrickson, C.L., Jackson, G.S.: Fourier Transform Ion Cyclotron Resonance Mass Spectrometry: A Primer. Mass Spectrom Rev. 17, 1–35 (1998)CrossRefPubMedGoogle Scholar
  46. 46.
    Contino, N.C., Jarrold, M.F.: Charge Detection Mass Spectrometry for Single Ions with a Limit of Detection of 30 Charges. Int J Mass Spectrom. 345–347, 153–159 (2013)CrossRefGoogle Scholar
  47. 47.
    Ledford, E.B., Rempel, D.L., Gross, M.L.: Space Charge Effects in Fourier Transform Mass Spectrometry. II. Mass Calibration. Anal Chem. 56, 2744–2748 (1984)CrossRefPubMedGoogle Scholar
  48. 48.
    Keifer, D.Z., Alexander, A.W., Jarrold, M.F.: Spontaneous Mass and Charge Losses from Single Multi-Megadalton Ions Studied by Charge Detection Mass Spectrometry. J Am Soc Mass Spectrom. 28, 498–506 (2017)CrossRefPubMedGoogle Scholar
  49. 49.
    Elliott, A.G., Harper, C.C., Lin, H., Williams, E.R.: Effects of Individual Ion Energies on Charge Measurements in Fourier Transform Charge Detection Mass Spectrometry (FT-CDMS). J Am Soc Mass Spectrom. 30, 946–955 (2018)CrossRefPubMedGoogle Scholar
  50. 50.
    Halim, M.A., Clavier, C., Dagany, X., Kerleroux, M., Dugourd, P., Dunbar, R.C., Antoine, R.: Infrared Laser Dissociation of Single Megadalton Polymer Ions in a Gated Electrostatic Ion Trap: The Added Value of Statistical Analysis of Individual Events. Phys Chem Chem Phys. 20, 11959–11966 (2018)Google Scholar

Copyright information

© American Society for Mass Spectrometry 2019

Authors and Affiliations

  1. 1.Department of ChemistryUniversity of CaliforniaBerkeleyUSA

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