Heterogeneous, high–molecular weight analytes often generate complex mass spectra characterized by substantial peak overlap in m/z space. The resulting inability to resolve charge states limits both the upper mass range and the degree of polydispersity accessible to conventional mass spectrometry. To address this challenge, several groups have developed approaches that directly measure both m/z and charge for individual ions, collectively known as charge detection mass spectrometry (CDMS). CDMS has proven particularly effective for analyzing protein complexes and their aggregates, intact virus capsids, nanoparticles, and even water droplets in the gigadalton mass range.

Our group is extending these capabilities to enable quantitative analysis of synthetically prepared polymer size distributions and polydispersity; to characterize the biophysical properties of glycosaminoglycans and their complexes with proteins and chemokines; and to investigate the degradation of multi-megadalton sized protein aggregates implicated in neurodegenerative disease. We are also expanding the CDMS toolset by developing novel hardware and software strategies for improved measurement and interpretation of heavy, heterogeneous ions.

Related Publications

• Atmospheric Sampling Mass Spectrometers Activate and Ionize Neutral Water Microdroplets to MeV Energies and up to 200,000+ Charges: Implications for Water Stability and Unusual Chemistry in Microdroplets
  McPartlan, M.S.; Chen, C.J.; Harper, C.C.; Miller, Z.M.; Robler, J.; Avadhani, V.S.; Pedder, R.E.; Metzler, L.J. & Williams, E.R. ACS Cent. Sci. 2025  
• Charge Detection Mass Spectrometry Reveals Conformational Heterogeneity in Megadalton-Sized Monoclonal Antibody Aggregates
  Jordan, J.S.; Harper, C.C.; Zhang, F.; Kofman, E.; Li, M.; Sathiyamoorthy, K.; Zaragoza, J.P.; Fayadat-Dilman, L. & Williams, E.R. J. Am. Chem. Soc. 2024
• Accurate Sizing of Nanoparticles Using a High-Throughput Charge Detection Mass Spectrometer without Energy Selection
  Harper, C.C.; Miller, Z.M.; McPartlan, M.S.; Jordan, J.S.; Pedder, R.E. & Williams, E.R. ACS Nano. 2023
• CDMS Analysis of Intact 19S, 20S, 26S, and 30S Proteasomes: Evidence for Higher-Order 20S Assemblies at a Low pH
  Anthony, A.J.; Gautam, A.K.S.; Miller, L.M.; Ma, Y.; Hardwick, A.G.; Sharma, A.; Ghatek, S.; Matouschek, A.; Jarrold, M.F. & Clemmer, D. E. Anal. Chem. 2023 
• Characterizing Heterogeneous Mixtures of Assembled States of the Tobacco Mosaic Virus Using Charge Detection Mass Spectrometry
  Bischoff, A.J.; Harper, C.C.; Williams, E.R. & Francis, M.B. J. Am. Chem. Soc. 2022 
• Applications of Charge Detection Mass Spectrometry in Molecular Biology and Biotechnology
  Jarrold, M.F. Chem. Rev. 2021  
• Resolving heterogeneous macromolecular assemblies by Orbitrap-based single-particle charge detection mass spectrometry
  Wörner, T.; Snijder, J.; Bennett, A.; Agbandje-McKenna, M.; Makarov, A.A. & Heck, A. Nat. Methods. 2020
• Charge Detection Mass Spectrometry for Single Ions with a Limit of Detection of 30 Charges
  Contino, N.C. & Jarrold, M.F. Int. J. Mass Spectrom. 2013
• Charging megadalton poly(ethylene oxide)s by electrospray ionization. A charge detection mass spectrometry study
  Doussineau, T.; Kerleroux, M.; Dagany, X.; Clavier, C.; Barbaire, M.; Maurelli, J.; Antoine, R. & Dugourd, P. Rapid Commun. Mass Spectrom. 2011