Collision induced unfolding of isolated proteins in the gas phase: past, present, and future
Open accessAbstract
Rapidly characterizing the three-dimensional structures of proteins and the multimeric machines they form remains one of the great challenges facing modern biological and medical sciences. Ion mobility-mass spectrometry based techniques are playing an expanding role in characterizing these functional complexes, especially in drug discovery and development workflows. Despite this expansion, ion mobility-mass spectrometry faces many challenges, especially in the context of detecting small differences in protein tertiary structure that bear functional consequences. Collision induced unfolding is an ion mobility-mass spectrometry method that enables the rapid differentiation of subtly-different protein isoforms based on their unfolding patterns and stabilities. In this review, we summarize the modern implementation of such gas-phase unfolding experiments and provide an overview of recent developments in both methods and applications.
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Collision-induced unfolding (CIU) allows concomitant study of conformational stability, providing more details than IM alone.
“In addition, collision-induced unfolding (CIU), i.e., increasing the internal energy of an ion prior to IM-MS analysis, allows concomitant study of conformational stability, providing more details than IM alone.”
From Higher-order structural characterisation of native proteins and complexes by top-down mass spectrometry (2020) · cites this paper as [26]
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Vallejo, D. D., Kang, J., Coghlan, J., Ramírez, C. R., Polasky, D. A., Kurulugama, R. T., Fjeldsted, J. C., Schwendeman, A. A., & Ruotolo, B. T. (2021) · Analytical Chemistry · doi:10.1021/acs.analchem.1c03946 · Cited by 30 · see citing works
Self-citationRecent technological developments for native mass spectrometry
Webb, I. K. (2022) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2021.140732 · Cited by 29 · see citing works
Using 10,000 Fragment Ions to Inform Scoring in Native Top-down Proteomics
Ives, A. N., Su, T., Durbin, K. R., Early, B. P., Seckler, H. D. S., Fellers, R. T., LeDuc, R. D., Schachner, L. F., Patrie, S. M., & Kelleher, N. (2020) · Journal of the American Society for Mass Spectrometry · doi:10.1021/jasms.0c00026 · Cited by 28 · see citing works
Dissecting the structural heterogeneity of proteins by native mass spectrometry
Reid, D. J., Thibert, S. M., & Zhou, M.-W. (2023) · Protein Science · doi:10.1002/pro.4612 · Cited by 23 · see citing works
“Nevertheless, IgGs with minor structural differences have displayed different gasphase unfolding behaviors (Dixit et al., 2018; Tian et al., 2015), implying an indirect link between solution and gas-phase structures.”
BackgroundFiorentino, F., Rotili, D., & Mai, A. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103548 · Cited by 29 · see citing works
Kerr, R. A., Keire, D. A., & Ye, H. (2019) · mAbs · doi:10.1080/19420862.2019.1599632 · Cited by 28 · see citing works
“CIU leverages the capability of IM-MS to measure changes in structural conformation as a function of gas-phase collisional activation.(38) Changes in the structural stability of the gas phase ions can then be quantified against reference datasets using difference plots and scaled deviation score (SDS) values.”
MethodFantin, S. M., Parson, K. F., Yadav, P. K., Juliano, B. R., Li, G., Sanders, C. R., Ohi, M. D., & Ruotolo, B. T. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2015331118 · Cited by 28 · see citing works
Self-citationDeslignière, E., Ehkirch, A., Duivelshof, B. L., Toftevall, H., Sjögren, J., Guillarme, D., D’Atri, V., Beck, A., Hernandez‐Alba, O., & Cianférani, S. (2021) · Pharmaceuticals · doi:10.3390/ph14060498 · Cited by 28 · see citing works
“IM-based collision-induced unfolding (CIU) approaches have proved to be efficient to circumvent poor linear travelling-wave IM (TWIMS) resolution, offering further insight into gas-phase behavior upon ion activation in the instrument trap cell [34].”
BackgroundEnhanced oligomerization of full-length RAGE by synergy of the interaction of its domains
Moysa, A. A., Hammerschmid, D., Szczepanowski, R. H., Sobott, F., & Dadlez, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-56993-9 · Cited by 27 · see citing works
Ag+ Ion Binding to Human Metallothionein-2A Is Cooperative and Domain Specific
Dong, S., Shirzadeh, M., Fan, L., Laganowsky, A. D., & Russell, D. H. (2020) · Analytical Chemistry · doi:10.1021/acs.analchem.0c00829 · Cited by 27 · see citing works
Assembly of Model Membrane Nanodiscs for Native Mass Spectrometry
Kostelic, M. M., Zak, C. K., Jayasekera, H. S., & Marty, M. T. (2021) · Analytical Chemistry · doi:10.1021/acs.analchem.1c00735 · Cited by 26 · see citing works
“The membrane scaffold protein (MSP), MSP1D1(-), was expressed, purified, and used in the assembly of nanodiscs as previously described.(1-2) Briefly, MSP1D1 was expressed in E.”
MethodSurface-induced dissociation of protein complexes on a cyclic ion mobility spectrometer
Snyder, D. T., Jones, B. J., Lin, Y.-F., Cooper-Shepherd, D. A., Hewitt, D., Wildgoose, J. L., Brown, J. M., Langridge, J., & Wysocki, V. H. (2021) · The Analyst · doi:10.1039/d1an01407b · Cited by 28 · see citing works
Gadkari, V. V., Juliano, B. R., Mallis, C. S., May, J. C., Kurulugama, R. T., Fjeldsted, J. C., MCLEAN, J. A. J., Russell, D. H., & Ruotolo, B. T. (2022) · The Analyst · doi:10.1039/d2an01452a · Cited by 25 · see citing works
Self-citationChen, S., Wu, D., Robinson, C. V., & Struwe, W. B. (2021) · Analytical Chemistry · doi:10.1021/acs.analchem.1c01460 · Cited by 24 · see citing works
Vallejo, D. D., Jeon, C. K., Parson, K. F., Herderschee, H. R., Eschweiler, J. D., Filoti, D. I., & Ruotolo, B. T. (2022) · Analytical Chemistry · doi:10.1021/acs.analchem.2c00160 · Cited by 24 · see citing works
Self-citationD’Amico, C. I., Polasky, D. A., Steyer, D. J., Ruotolo, B. T., & Kennedy, R. T. (2022) · Analytical Chemistry · doi:10.1021/acs.analchem.2c02307 · Cited by 24 · see citing works
Self-citationStructural studies of supramolecular complexes and assemblies by ion mobility mass spectrometry
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Sipe, S. N., Lancaster, E. B., Butalewicz, J. P., Whitman, C. P., & Brodbelt, J. S. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c03564 · Cited by 23 · see citing works
Sanders, H. M., Jovcevski, B., Carver, J. A., & Pukala, T. L. (2020) · Biochemical Journal · doi:10.1042/bcj20190638 · Cited by 23 · see citing works
Ion exchange chromatography of biotherapeutics: Fundamental principles and advanced approaches
Imiołek, M., Fekete, S., Rudaz, S. L., & Guillarme, D. (2025) · Journal of Chromatography A · doi:10.1016/j.chroma.2025.465672 · Cited by 22 · see citing works
Cui, M., & Du, Y. (2024) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2024.117701 · Cited by 22 · see citing works
Ion Mobility-Mass Spectrometry in Metabolomic, Lipidomic, and Proteomic Analyses
Chouinard, C. D., Nagy, G., Smith, R. D., & Baker, E. S. (2018) · Comprehensive analytical chemistry · doi:10.1016/bs.coac.2018.11.001 · Cited by 21 · see citing works
Formation and characterization of polymetallic {CrxMy} rings in vacuo
Geue, N., Timco, G. A., Whitehead, G. F. S., McInnes, E. J. L., Burton, N. A., Winpenny, R. E. P., & Barran, P. E. (2023) · Nature Synthesis · doi:10.1038/s44160-023-00383-7 · Cited by 20 · see citing works
“Particularly for proteins, the term ‘collisioninduced unfolding’ was coined to describe this behaviour similar to denaturation 1 .”
Collision Cross Sections for Native Proteomics: Challenges and Opportunities
Ruotolo, B. T. (2021) · Journal of Proteome Research · doi:10.1021/acs.jproteome.1c00686 · Cited by 20 · see citing works
Self-citationBiopharmaceutical Quality Control with Mass Spectrometry
Liu, S., & Schulz, B. L. (2021) · Bioanalysis · doi:10.4155/bio-2021-0123 · Cited by 19 · see citing works
Mass spectrometric insights into protein aggregation
Pukala, T. L. (2023) · Essays in Biochemistry · doi:10.1042/ebc20220103 · Cited by 19 · see citing works
Castel, J.-G., Delaux, S., Hernandez‐Alba, O., & Cianférani, S. (2023) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2023.115696 · Cited by 19 · see citing works
VHH characterization.Recombinant VHHs: Production, characterization and affinity
Chabrol, E., Stojko, J., Nicolas, A., Botzanowski, T., Fould, B., Antoine, M., Cianférani, S., Ferry, G., & Boutin, J. A. (2019) · Analytical Biochemistry · doi:10.1016/j.ab.2019.113491 · Cited by 18 · see citing works
Effects of Detergent on α-Synuclein Structure: A Native MS-Ion Mobility Study
Moons, R., Bruijne, R. V. D. W.-D., Maudsley, S. R., Lemière, F., Lambeir, A., & Sobott, F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21217884 · Cited by 19 · see citing works
“In these CIU plots, increasing the trap collision energy in steps of 5 V will eventually result in the loss of detergent interaction, generally indicated by the CID50 value when 50% of the ligand is lost, usually concomitant with protein unfolding [47].”
Collision-Induced Unfolding Is Sensitive to the Polarity of Proteins and Protein Complexes
Hong, S., & Bush, M. F. (2019) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-019-02326-z · Cited by 18 · see citing works
“Monitoring changes in conformation (collision-induced unfolding, CIU [17]) and extents of dissociation (collision-induced dissociation, CID) as a function of energy can provide information that is complementary to the associated IM and MS characterization of minimally activated ions.”
BackgroundCellular synthesis of protein pretzelanes
Bai, X., Liu, Y., Lee, J., Fang, J., Wu, W., Seo, J., & Zhang, W. (2022) · Giant · doi:10.1016/j.giant.2022.100092 · Cited by 18 · see citing works
van Schaick, G., Domínguez‐Vega, E., Castel, J.-G., Wuhrer, M., Hernandez‐Alba, O., & Cianférani, S. (2023) · Analytical Chemistry · doi:10.1021/acs.analchem.2c03163 · Cited by 18 · see citing works
Anders, A. G., Tidwell, E. D., Gadkari, V. V., Koutmos, M., & Ruotolo, B. T. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.3c09230 · Cited by 18 · see citing works
Self-citationKulesza, A. J., Marklund, E. G., MacAleese, L., Chirot, F., & Dugourd, P. (2018) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.8b03825 · Cited by 17 · see citing works
Rabuck-Gibbons, J. N., Lodge, J. M., Mapp, A. K., & Ruotolo, B. T. (2018) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-018-2043-6 · Cited by 18 · see citing works
“CIU has been used to distinguish between modes of ATP-competitive kinase inhibitors [25], in biosimilar analysis [26, 27], to assess biotherapeutics [28], and to probe the binding of specific lipids to membrane protein complexes [29–33].”
Self-citationStructural Analysis of the Effect of a Dual-FLAG Tag on Transthyretin
Shirzadeh, M., Poltash, M. L., Laganowsky, A. D., & Russell, D. H. (2020) · Biochemistry · doi:10.1021/acs.biochem.0c00105 · Cited by 18 · see citing works
Collision-Induced Unfolding Differentiates Functional Variants of the KCNQ1 Voltage Sensor Domain
Fantin, S. M., Huang, H., Sanders, C. R., & Ruotolo, B. T. (2020) · Journal of the American Society for Mass Spectrometry · doi:10.1021/jasms.0c00288 · Cited by 18 · see citing works
Self-citationLC-MS characterization of antibody-based therapeutics
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Villafuerte-Vega, R. C., Li, H. W., Slaney, T. R., Chennamsetty, N., Chen, G., Tao, L., & Ruotolo, B. T. (2023) · Analytical Chemistry · doi:10.1021/acs.analchem.3c00344 · Cited by 17 · see citing works
Self-citationJuliano, B. R., Keating, J. W., Li, H. W., Anders, A. G., Xie, Z., & Ruotolo, B. T. (2023) · Analytical Chemistry · doi:10.1021/acs.analchem.3c03788 · Cited by 18 · see citing works
Self-citationShepherd, S. O., Green, A. W., Resendiz, E. S., Newton, K. R., Kurulugama, R. T., & Prell, J. S. (2024) · Journal of the American Society for Mass Spectrometry · doi:10.1021/jasms.3c00371 · Cited by 17 · see citing works
Makey, D. M., Gadkari, V. V., Kennedy, R. T., & Ruotolo, B. (2024) · Analytical Chemistry · doi:10.1021/acs.analchem.4c00477 · Cited by 16 · see citing works
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An Algorithm for Building Multi-State Classifiers Based on Collision-Induced Unfolding Data
Polasky, D. A., Dixit, S. M., Vallejo, D. D., Kulju, K. D., & Ruotolo, B. T. (2019) · Analytical Chemistry · doi:10.1021/acs.analchem.9b02650 · Cited by 16 · see citing works
Self-citationInsights on the Conformational Ensemble of Cyt C Reveal a Compact State during Peroxidase Activity
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Effects of charge on protein ion structure: Lessons from cation‐to‐anion, proton‐transfer reactions
Gozzo, T. A., & Bush, M. F. (2023) · Mass Spectrometry Reviews · doi:10.1002/mas.21847 · Cited by 15 · see citing works
Lantz, C., Lopez, J., Goring, A. K., Zenaidee, M. A., Biggs, K. E., Whitelegge, J. P., Loo, R. R. O., Klärner, F., Schrader, T. H., Bitan, G., et al. (2023) · Journal of the American Society for Mass Spectrometry · doi:10.1021/jasms.3c00281 · Cited by 17 · see citing works
- Authors
- Dixit, S. M., Polasky, D. A., & Ruotolo, B. T.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Ruotolo, Brandon T
- Venue
- Current Opinion in Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 42
- Pages
- 93-100
- ISSN
- 1367-5931 (ISSN-L)
- PMC
- PMC5828980
- OpenAlex
- W2772936471
- Cited by
- 235
- References
- 48
- Citations by year
- 2026: 21 · 2025: 24 · 2024: 35 · 2023: 28 · 2022: 24 · 2021: 35 · 2020: 31 · 2019: 26 · 2018: 10 · 2015: 1
- FWCI
- 2.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 307 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Current Opinion in Chemical Biology (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation (1253384)
- National Institutes of Health
- NIGMS (R01 GM095832)
- Eli Lilly and Company
- Agilent Technologies
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- collision-induced unfolding, ion mobility mass spectrometry, protein tertiary structure, protein isoforms, protein stability, protein complexes, drug discovery
- MeSH terms
- Ion Mobility Spectrometry, Biological Products, Gases, Protein Conformation, Proteins, Mass Spectrometry, Protein Structure, Secondary, Protein Isoforms, Drug Discovery, High-Throughput Screening Assays, Protein Unfolding
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