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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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“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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Lanucara, F., Holman, S. W., Gray, C. J., & Eyers, C. E. (2014) · Nature Chemistry · doi:10.1038/nchem.1889 · Cited by 901 · cited 1×
“charge ratio and reports ion size in terms of an orientationally-averaged collision cross section (CCS), has also been widely deployed in combination with MS as a platform for structural biology [5].”
MethodMembrane proteins bind lipids selectively to modulate their structure and function
Laganowsky, A. D., Reading, E., Allison, T. M., Ulmschneider, M. B., Degiacomi, M. T., Baldwin, A. J., & Robinson, C. V. (2014) · Nature · doi:10.1038/nature13419 · Cited by 804
Evidence for Macromolecular Protein Rings in the Absence of Bulk Water
Ruotolo, B. T., Giles, K., Campuzano, I. D. G., Sandercock, A. M., Bateman, R. H., & Robinson, C. V. (2005) · Science · doi:10.1126/science.1120177 · Cited by 597
Self-citationNaked Protein Conformations: Cytochrome c in the Gas Phase
Clemmer, D. E., Hudgins, R. R., & Jarrold, M. F. (1995) · Journal of the American Chemical Society · doi:10.1021/ja00145a037 · Cited by 493 · cited 3×
“However, as the size and complexity of biomolecules increases, IM-derived CCS values alone often yield insufficient information to define the structures of proteins in detail [7].”
BackgroundMethodProtein Structure in Vacuo: Gas-Phase Conformations of BPTI and Cytochrome c
Shelimov, K. B., Clemmer, D. E., Hudgins, R. R., & Jarrold, M. F. (1997) · Journal of the American Chemical Society · doi:10.1021/ja9619059 · Cited by 415 · cited 2×
“Collisional activation followed by IM-MS has been used to probe the conformations of proteins in the gas phase for nearly two decades [10,11].”
BackgroundMethodPace, C. N., Scholtz, J. M., & Grimsley, G. R. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.05.006 · Cited by 390 · cited 1×
“One such element is protein stability, often reported as a free energy of protein unfolding and represents one of the most widely utilized descriptors of protein structure [3].”
BackgroundGas-Phase Conformation of Biological Molecules: Bradykinin
Wyttenbach, T., von Helden, G., & Bowers, M. T. (1996) · Journal of the American Chemical Society · doi:10.1021/ja9535928 · Cited by 383 · cited 1×
“Prior to this recent period of expansion, IM-MS was used to primarily assign the conformations of peptides [6] and small proteins [7] in the gas phase.”
MethodKoeniger, S. L., Merenbloom, S. I., Valentine, S. J., Jarrold, M. F., Udseth, H. R., Smith, R. D., & Clemmer, D. E. (2006) · Analytical Chemistry · doi:10.1021/ac051060w · Cited by 275
Hall, Z., Politis, A., Bush, M. F., Smith, L. J., & Robinson, C. V. (2012) · Journal of the American Chemical Society · doi:10.1021/ja2096859 · Cited by 267
Ruotolo, B. T., Hyung, S., Robinson, P. M., Giles, K., Bateman, R. H., & Robinson, C. V. (2007) · Angewandte Chemie International Edition · doi:10.1002/anie.200702161 · Cited by 229
Self-citationTandem Mass Spectrometry Reveals the Quaternary Organization of Macromolecular Assemblies
Benesch, J. L. P., Aquilina, J. A., Ruotolo, B. T., Sobott, F., & Robinson, C. V. (2006) · Chemistry & Biology · doi:10.1016/j.chembiol.2006.04.006 · Cited by 225 · cited 2×
“The introduction of CIU enabled the direct observation of collisionally-activated protein assemblies, confirming that they populate partially folded intermediates that are stable on the millisecond timescale [8,12,26].”
BackgroundMethodSelf-citationShelimov, K. B., & Jarrold, M. F. (1997) · Journal of the American Chemical Society · doi:10.1021/ja962914k · Cited by 205 · cited 3×
“Collisional activation followed by IM-MS has been used to probe the conformations of proteins in the gas phase for nearly two decades [10,11].”
BackgroundMethodIMS−IMS and IMS−IMS−IMS/MS for Separating Peptide and Protein Fragment Ions
Merenbloom, S. I., Koeniger, S. L., Valentine, S. J., Plasencia, M. D., & Clemmer, D. E. (2006) · Analytical Chemistry · doi:10.1021/ac052208e · Cited by 203
Mass Spectrometry of Protein Complexes: From Origins to Applications
Mehmood, S., Allison, T. M., & Robinson, C. V. (2015) · Annual Review of Physical Chemistry · doi:10.1146/annurev-physchem-040214-121732 · Cited by 200
Hopper, J. T. S., & Oldham, N. J. (2009) · Journal of the American Society for Mass Spectrometry · doi:10.1016/j.jasms.2009.06.010 · Cited by 198
Felitsyn, N. M., Kitova, E. N., & Klassen, J. S. (2001) · Analytical Chemistry · doi:10.1021/ac0103975 · Cited by 172
Tian, Y., Han, L., Buckner, A. C., & Ruotolo, B. T. (2015) · Analytical Chemistry · doi:10.1021/acs.analchem.5b03291 · Cited by 169
Self-citationHyung, S., Robinson, C. V., & Ruotolo, B. T. (2009) · Chemistry & Biology · doi:10.1016/j.chembiol.2009.02.008 · Cited by 168 · cited 2×
“Collisional activation has long been used to probe the structure and stability of protein ions in the gas phase [8,9].”
BackgroundMethodSelf-citationQuantifying the stabilizing effects of protein–ligand interactions in the gas phase
Allison, T. M., Reading, E., Liko, I., Baldwin, A. J., Laganowsky, A. D., & Robinson, C. V. (2015) · Nature Communications · doi:10.1038/ncomms9551 · Cited by 158
Mass Spectrometry Methods for Studying Structure and Dynamics of Biological Macromolecules
Konermann, L., Vahidi, S., & Sowole, M. A. (2013) · Analytical Chemistry · doi:10.1021/ac4039306 · Cited by 140 · cited 1×
“Mass spectrometry (MS) has recently experienced a proliferation of structural biology related research, focusing primarily on heterogeneous proteins, protein complexes, and protein-ligand complexes due to its ability to access such mixtures with sensitivity, speed, and low limits of detection [4].”
BackgroundZhong, Y., Han, L., & Ruotolo, B. T. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201403784 · Cited by 137
Self-citationExploring the structure and function paradigm.
Redfern, O., Dessailly, B. H., & Orengo, C. (2008) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2008.05.007 · Cited by 133 · cited 1×
“In order to understand protein structure, its role in defining function, and any changes that may occur in disease states, it is essential to explore the connective biophysical parameters that link such elements of biophysics together [2].”
BackgroundEschweiler, J. D., Rabuck-Gibbons, J. N., Tian, Y., & Ruotolo, B. T. (2015) · Analytical Chemistry · doi:10.1021/acs.analchem.5b03292 · Cited by 124
Self-citationHaynes, S. E., Polasky, D. A., Dixit, S. M., Majmudar, J. D., Neeson, K., Ruotolo, B. T., & Martin, B. R. (2017) · Analytical Chemistry · doi:10.1021/acs.analchem.7b00112 · Cited by 105
Self-citationBound Anions Differentially Stabilize Multiprotein Complexes in the Absence of Bulk Solvent
Han, L., Hyung, S., Mayers, J. J. S., & Ruotolo, B. T. (2011) · Journal of the American Chemical Society · doi:10.1021/ja203527a · Cited by 99
Self-citationFolding of Protein Ions in the Gas Phase after Cation-to-Anion Proton-Transfer Reactions
Laszlo, K. J., Munger, E. B., & Bush, M. F. (2016) · Journal of the American Chemical Society · doi:10.1021/jacs.6b04282 · Cited by 87
Activation State-Selective Kinase Inhibitor Assay Based on Ion Mobility-Mass Spectrometry
Rabuck-Gibbons, J. N., Hyung, S., Ko, K. S., Fox, C. C., Soellner, M. B., & Ruotolo, B. T. (2013) · Analytical Chemistry · doi:10.1021/ac4012655 · Cited by 80
Self-citationA Multidimensional Analytical Comparison of Remicade and the Biosimilar Remsima
Pisupati, K., Tian, Y., Okbazghi, S. Z., Benet, A., Ackermann, R., Ford, M., Saveliev, S. V., Hosfield, C. M., Urh, M., Carlson, E. D., et al. (2017) · Analytical Chemistry · doi:10.1021/acs.analchem.6b04436 · Cited by 75
Self-citationPopa, V., Trecroce, D. A., McAllister, R. G., & Konermann, L. (2016) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.6b03035 · Cited by 73
Mass spectrometry locates local and allosteric conformational changes that occur on cofactor binding
Beveridge, R., Migas, L. G., Payne, K. A. P., Scrutton, N. S., Leys, D., & Barran, P. E. (2016) · Nature Communications · doi:10.1038/ncomms12163 · Cited by 73
Osadchy, M., & Kolodny, R. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102727108 · Cited by 71 · cited 1×
“The fundamental relationship between protein structure and function makes their study critical in ongoing efforts to understand both fundamental elements of biochemistry and human disease [1].”
BackgroundResidual counter ions can stabilise a large protein complex in the gas phase
Freeke, J., Robinson, C. V., & Ruotolo, B. T. (2009) · International Journal of Mass Spectrometry · doi:10.1016/j.ijms.2009.08.001 · Cited by 70
Self-citationBotzanowski, T., Erb, S., Hernandez‐Alba, O., Ehkirch, A., Colas, O., Wagner‐Rousset, E., Rabuka, D., Beck, A., Drake, P. M., & Cianférani, S. (2017) · mAbs · doi:10.1080/19420862.2017.1316914 · Cited by 68
Mehmood, S., Marcoux, J., Gault, J., Quigley, A., Michaelis, S., Young, S. G., Carpenter, E. P., & Robinson, C. V. (2016) · Nature Chemistry · doi:10.1038/nchem.2591 · Cited by 65
Eschweiler, J. D., Martini, R. M., & Ruotolo, B. T. (2016) · Journal of the American Chemical Society · doi:10.1021/jacs.6b11678 · Cited by 65
Self-citationAmphitrite: A program for processing travelling wave ion mobility mass spectrometry data
Sivalingam, G. N., Yan, J., Sahota, H., & Thalassinos, K. (2012) · International Journal of Mass Spectrometry · doi:10.1016/j.ijms.2012.09.005 · Cited by 62
Niu, S., & Ruotolo, B. T. (2015) · Protein Science · doi:10.1002/pro.2699 · Cited by 59
Self-citationByrne, D. P., Vonderach, M., Ferries, S., Brownridge, P., Eyers, C. E., & Eyers, P. A. (2016) · Biochemical Journal · doi:10.1042/bcj20160648 · Cited by 56
Liu, Y., Cong, X., Liu, W., & Laganowsky, A. D. (2016) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-016-1555-1 · Cited by 56
Bound Cations Significantly Stabilize the Structure of Multiprotein Complexes in the Gas Phase
Han, L., Hyung, S., & Ruotolo, B. T. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201109127 · Cited by 52
Self-citationA Charge Moving Algorithm for Molecular Dynamics Simulations of Gas-Phase Proteins
Fegan, S. K., & Thachuk, M. (2013) · Journal of Chemical Theory and Computation · doi:10.1021/ct300906a · Cited by 48
Pierson, N. A., & Clemmer, D. E. (2014) · International Journal of Mass Spectrometry · doi:10.1016/j.ijms.2014.07.012 · Cited by 47
Evaluation of Ion Mobility-Mass Spectrometry for Comparative Analysis of Monoclonal Antibodies
Ferguson, C. N., & Gucinski-Ruth, A. C. (2016) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-016-1369-1 · Cited by 32
Ion Mobility and Mass Spectrometry Measurements of the Humanized IgGk NIST Monoclonal Antibody
Campuzano, I. D. G., Larriba‐Andaluz, C., Bagal, D., & Schnier, P. D. (2015) · ACS symposium series · doi:10.1021/bk-2015-1202.ch004 · Cited by 31
Wagner, N. D., Kim, D., & Russell, D. H. (2016) · Analytical Chemistry · doi:10.1021/acs.analchem.6b00871 · Cited by 27
Samulak, B. M., Niu, S., Andrews, P., & Ruotolo, B. T. (2016) · Analytical Chemistry · doi:10.1021/acs.analchem.6b00518 · Cited by 17
Self-citationControlling Dissociation Channels of Gas-Phase Protein Complexes Using Charge Manipulation
Fegan, S. K., & Thachuk, M. (2014) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-014-0831-1 · Cited by 7
Description and control of dissociation channels in gas-phase protein complexes
Thachuk, M., Fegan, S. K., & Raheem, N. (2016) · The Journal of Chemical Physics · doi:10.1063/1.4960615 · Cited by 6
Cited by
Sorted by citations
Ion Activation Methods for Peptides and Proteins
Brodbelt, J. S. (2015) · Analytical Chemistry · doi:10.1021/acs.analchem.5b04563 · Cited by 259
Protein–Small Molecule Interactions in Native Mass Spectrometry
Bennett, J. L., Nguyen, G. T. H., & Donald, W. A. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00293 · Cited by 161
Zhou, M., Lantz, C., Brown, K. A., Ge, Y., Paša-Tolić, L., Loo, J. A., & Lermyte, F. (2020) · Chemical Science · doi:10.1039/d0sc04392c · Cited by 146
Lermyte, F., Tsybin, Y. O., O’Connor, P. B., & Loo, J. A. (2019) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-019-02201-x · Cited by 132
“If this is performed in conjunction with, and prior to, ion mobility measurements, this type of collision-induced unfolding (CIU) experiment can provide valuable insight into (changes in) the stability of various elements of protein structure in the gas phase [17].”
BackgroundNative Mass Spectrometry: Recent Progress and Remaining Challenges
Karch, K. R., Snyder, D. T., Harvey, S. R., & Wysocki, V. H. (2022) · Annual Review of Biophysics · doi:10.1146/annurev-biophys-092721-085421 · Cited by 149
“However, CIU can provide information on the overall conformational landscape and stability of a protein upon ligand binding (33, 45).”
BackgroundMethod
Metadata
- 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
- 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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