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While some of these conformations are functionally important, others (e.g., preaggregative states), can adversely affect protein function. In monoclonal antibody (mAb)-based biotherapeutics such structural polydispersity is essential for native function but requires advanced biophysical and analytical techniques to assess and properly engineer optimal therapeutics. Methods such as native mass spectrometry (MS) and ion mobility-mass spectrometry (IM-MS) have become increasingly valuable for studying protein structure. Collision induced unfolding (CIU), an IM-MS assay, is frequently used to examine global higher-order structures of proteins. However, standard CIU assays are fundamentally limited by the IM resolution achieved for the precursor ion population, which may contain multiple conformers with similar collision cross sections. In this report, we use cyclic IM-MS (cIM-MS) to develop and conduct IM-selected CIU assays, which show dramatically enhanced capabilities for analyzing structurally polydisperse samples. To develop the IM-CIU approach, we investigate the model protein bovine serum albumin under both low and neutral pH conditions, demonstrating that IM-CIU can accurately identify domain III as the most perturbed region of the protein under these conditions. Additionally, we apply IM-CIU to analyze interleukin dimers, previously linked in therapeutic fusion protein constructs, and demonstrate that they exist in two distinct solution-based conformations. We conclude by outlining the fundamental principles of the IM-CIU method, highlighting its ability to resolve proteins with near-identical collision cross sections, and discussing its potential impact on the development of future pharmaceutical applications.<\/jats:p>","DOI":"10.1021\/jasms.6c00275","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T22:52:59Z","timestamp":1788216779000},"page":"2525-2533","source":"Crossref","is-referenced-by-count":0,"title":["Ion Mobility-Collision\nInduced Unfolding Detects Stability\nShifts within Hidden Protein Conformer Families"],"prefix":"10.1021","volume":"37","author":[{"given":"Addison E.","family":"Bergman","sequence":"first","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2991-6760","authenticated-orcid":true,"given":"Devin M.","family":"Makey","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosendo C.","family":"Villafuerte-Vega","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4938-5821","authenticated-orcid":true,"given":"Thomas R.","family":"Slaney","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb , , , ,","place":["New Brunswick, New Jersey, United States, 08903"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naresh","family":"Chennamsetty","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb , , , ,","place":["New Brunswick, New Jersey, United States, 08903"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guodong","family":"Chen","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb , , , ,","place":["New Brunswick, New Jersey, United States, 08903"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9343-7011","authenticated-orcid":true,"given":"Li","family":"Tao","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb , , , ,","place":["New Brunswick, New Jersey, United States, 08903"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6084-2328","authenticated-orcid":true,"given":"Brandon T.","family":"Ruotolo","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"issue":"11","key":"2026100710073409300_cit1","doi-asserted-by":"publisher","first-page":"6516","DOI":"10.1021\/acs.chemrev.5b00562","article-title":"Protein Ensembles: How Does Nature\nHarness Thermodynamic Fluctuations for Life? The Diverse Functional\nRoles of Conformational Ensembles in the Cell","volume":"116","author":"Wei","year":"2016","journal-title":"Chem. Rev."},{"issue":"0","key":"2026100710073409300_cit2","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1101\/SQB.1963.028.01.060","article-title":"The Genetic Control of Tertiary Protein\nStructure: Studies With Model Systems","volume":"28","author":"Epstein","year":"1963","journal-title":"Cold\nSpring Harbor Symp. Quant. Biol."},{"issue":"2","key":"2026100710073409300_cit3","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.ijpharm.2010.02.025","article-title":"Protein Aggregation-Pathways\nand\nInfluencing Factors","volume":"390","author":"Wang","year":"2010","journal-title":"Int. J. Pharm."},{"key":"2026100710073409300_cit4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2016\/5358272","article-title":"Posttranslational\nModifications and the Immunogenicity of Biotherapeutics","volume":"2016","author":"Jefferis","year":"2016","journal-title":"J. Immunol. Res."},{"issue":"7","key":"2026100710073409300_cit5","doi-asserted-by":"publisher","first-page":"2426","DOI":"10.1002\/jps.21180","article-title":"Heterogeneity\nof Monoclonal Antibodies","volume":"97","author":"Liu","year":"2008","journal-title":"J. Pharm. Sci."},{"issue":"7","key":"2026100710073409300_cit6","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1016\/j.tibtech.2014.05.005","article-title":"Therapeutic\nProtein Aggregation: Mechanisms, Design, and Control","volume":"32","author":"Roberts","year":"2014","journal-title":"Trends Biotechnol."},{"issue":"1","key":"2026100710073409300_cit7","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.xphs.2019.08.009","article-title":"Physicochemical Stability of Monoclonal Antibodies:\nA Review","volume":"109","author":"Le Basle","year":"2020","journal-title":"J. Pharm. Sci."},{"issue":"1","key":"2026100710073409300_cit8","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.ijpharm.2018.08.043","article-title":"Protein Aggregation\n\u2013 Mechanisms, Detection,\nand Control","volume":"550","author":"Wang","year":"2018","journal-title":"Int. J. 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Soc.\nMass Spectrom."},{"issue":"8","key":"2026100710073409300_cit35","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1080\/19420862.2019.1668226","article-title":"Direct Measurement\nof Light and Heavy\nAntibody Chains Using Ion Mobility and Middle-down Mass Spectrometry","volume":"11","author":"Melani","year":"2019","journal-title":"mAbs"},{"issue":"12","key":"2026100710073409300_cit36","doi-asserted-by":"publisher","first-page":"140697","DOI":"10.1016\/j.bbapap.2021.140697","article-title":"Current Status and\nFuture Prospects for Ion-Mobility Mass Spectrometry in the Biopharmaceutical\nIndustry","volume":"1869","author":"Skeene","year":"2021","journal-title":"Biochim. Biophys. Acta - Proteins\nProteom."},{"issue":"15","key":"2026100710073409300_cit37","doi-asserted-by":"publisher","first-page":"8865","DOI":"10.1021\/acs.analchem.8b00912","article-title":"Native Mass\nSpectrometry, Ion Mobility, and Collision-Induced Unfolding for Conformational\nCharacterization of IgG4Monoclonal Antibodies","volume":"90","author":"Hernandez-Alba","year":"2018","journal-title":"Anal. Chem."},{"issue":"24","key":"2026100710073409300_cit38","doi-asserted-by":"publisher","first-page":"10003","DOI":"10.1021\/acs.analchem.4c01408","article-title":"Ion Mobility-Mass\nSpectrometry and Collision-Induced Unfolding Rapidly Characterize\nthe Structural Polydispersity and Stability of an Fc-Fusion Protein","volume":"96","author":"Villafuerte-Vega","year":"2024","journal-title":"Anal. 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Chem."},{"key":"2026100710073409300_cit41","first-page":"75","article-title":"Ion Mobility and Mass Spectrometry\nMeasurements of the Humanized IgGk NIST Monoclonal Antibody","volume-title":"ACS Symposium Series","author":"Campuzano","year":"2015"},{"issue":"7","key":"2026100710073409300_cit42","doi-asserted-by":"publisher","DOI":"10.1002\/jms.5059","article-title":"Recent Advances in Gas Phase Unfolding: Instrumentation\nand Applications","volume":"59","author":"Matney","year":"2024","journal-title":"J. Mass Spectrom."},{"key":"2026100710073409300_cit43","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.cbpa.2017.11.010","article-title":"Collision Induced Unfolding of Isolated\nProteins in the Gas Phase: Past, Present, and Future","volume":"42","author":"Dixit","year":"2018","journal-title":"Curr. Opin. Chem. Biol."},{"issue":"6","key":"2026100710073409300_cit44","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1016\/j.chembiol.2006.04.006","article-title":"Tandem\nMass Spectrometry Reveals the Quaternary Organization of Macromolecular\nAssemblies","volume":"13","author":"Benesch","year":"2006","journal-title":"Chemistry & Biology"},{"issue":"4","key":"2026100710073409300_cit45","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/j.chembiol.2009.02.008","article-title":"Gas-Phase\nUnfolding and Disassembly\nReveals Stability Differences in Ligand-Bound Multiprotein Complexes","volume":"16","author":"Hyung","year":"2009","journal-title":"Chemistry & Biology"},{"issue":"18","key":"2026100710073409300_cit46","doi-asserted-by":"publisher","first-page":"6745","DOI":"10.1021\/acs.analchem.2c00160","article-title":"Ion Mobility\u2013Mass\nSpectrometry Reveals the Structures and Stabilities of Biotherapeutic\nAntibody Aggregates","volume":"94","author":"Vallejo","year":"2022","journal-title":"Anal. Chem."},{"key":"2026100710073409300_cit47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ijms.2017.12.005","article-title":"Collision Induced\nUnfolding Detects Subtle Differences\nin Intact Antibody Glycoforms and Associated Fragments","volume":"425","author":"Tian","year":"2018","journal-title":"Int. J. Mass Spectrom."},{"issue":"48","key":"2026100710073409300_cit48","doi-asserted-by":"publisher","first-page":"16166","DOI":"10.1021\/acs.analchem.1c03946","article-title":"Collision-Induced\nUnfolding Reveals\nStability Differences in Infliximab Therapeutics under Native and\nHeat Stress Conditions","volume":"93","author":"Vallejo","year":"2021","journal-title":"Anal. Chem."},{"issue":"13","key":"2026100710073409300_cit49","doi-asserted-by":"publisher","first-page":"8827","DOI":"10.1021\/acs.analchem.0c00293","article-title":"Middle Level\nIM\u2013MS and CIU Experiments for Improved\nTherapeutic Immunoglobulin Subclass Fingerprinting","volume":"92","author":"Botzanowski","year":"2020","journal-title":"Anal. Chem."},{"key":"2026100710073409300_cit50","doi-asserted-by":"publisher","DOI":"10.26434\/chemrxiv-2023-44qm1-v2","article-title":"Collision\nInduced Unfolding Reveals Disease-Associated Stability Shifts in Mitochondrial\ntRNAs","author":"Anders","year":"2023","journal-title":"ChemRxiv"},{"issue":"22","key":"2026100710073409300_cit51","doi-asserted-by":"publisher","first-page":"7981","DOI":"10.1021\/acs.analchem.2c00928","article-title":"Combination\nof IM-Based Approaches to Unravel the Coexistence of Two Conformers\non a Therapeutic Multispecific mAb","volume":"94","author":"Deslignie\u0300re","year":"2022","journal-title":"Anal. 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