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Disease progression is linked to the transition of \u03b1-syn from native to misfolded conformations, although the mechanisms underlying this process remain unclear. An effective method for investigating protein dynamics is native mass spectrometry, specifically when coupled with ion mobility-mass spectrometry (IM-MS) to examine differences in the shape and size of various analytes. In this study, variable-temperature electrospray ionization ion mobility-mass spectrometry (vT-ESI-IM-MS) was used to investigate the conformational dynamics of wild-type and A30P \u03b1-syn in the presence and absence of five osmolytes trimethylamine-N-oxide (TMAO), urea, guanidine, 1-dodecylguanidine (dodine), and arginine. For both \u03b1-syn variants, the abundance of extended conformers increased with temperature in the absence of osmolytes, consistent with temperature-dependent conformational shifts. This study shows osmolytes significantly alter conformational distributions and temperature-dependent responses, with dodine promoting extended conformations and guanidine producing the lowest abundance of extended states. These results demonstrate the utility of vT-ESI-IM-MS for probing IDP dynamics and highlight the influence of osmolytes on IDP conformational behavior.<\/jats:p>","DOI":"10.1021\/acs.jpcb.6c04859","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T14:25:30Z","timestamp":1791901530000},"page":"11122-11131","source":"Crossref","is-referenced-by-count":0,"title":["Influence of Temperature\nand Osmolytes on Conformational\nDynamics of Alpha Synuclein"],"prefix":"10.1021","volume":"130","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1143-6953","authenticated-orcid":true,"given":"Jared","family":"Hampton","sequence":"first","affiliation":[{"name":"Texas A&M University , , , ,","place":["College Station, Texas, United States, 77843"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Lynch","sequence":"additional","affiliation":[{"name":"Texas A&M University , , , ,","place":["College Station, Texas, United States, 77843"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7894-4920","authenticated-orcid":true,"given":"Robert L.","family":"Rider","sequence":"additional","affiliation":[{"name":"Texas A&M University , , , ,","place":["College Station, Texas, United States, 77843"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1657-8148","authenticated-orcid":true,"given":"Carter","family":"Lantz","sequence":"additional","affiliation":[{"name":"Texas A&M University , , , ,","place":["College Station, Texas, United States, 77843"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyu","family":"Xi","sequence":"additional","affiliation":[{"name":"Texas A&M University , , , ,","place":["College Station, Texas, United States, 77843"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0830-3914","authenticated-orcid":true,"given":"David H.","family":"Russell","sequence":"additional","affiliation":[{"name":"Texas A&M University , , , ,","place":["College Station, Texas, United States, 77843"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,13]]},"reference":[{"key":"2026102207420637200_cit1","doi-asserted-by":"publisher","first-page":"100358","DOI":"10.1016\/j.jbc.2021.100358","article-title":"Cross-seeding\nof alpha-synuclein aggregation by amyloid fibrils of food proteins","volume":"296","author":"Vaneyck","year":"2021","journal-title":"J. Biol. Chem."},{"issue":"11","key":"2026102207420637200_cit2","doi-asserted-by":"publisher","first-page":"5405","DOI":"10.3390\/ijms26115405","article-title":"alpha-Synuclein\nPathology in Synucleinopathies: Mechanisms,\nBiomarkers, and Therapeutic Challenges","volume":"26","author":"Arias-Carrion","year":"2025","journal-title":"Int.\nJ. Mol. Sci."},{"key":"2026102207420637200_cit3","doi-asserted-by":"publisher","first-page":"72","DOI":"10.3389\/fnagi.2020.00072","article-title":"Protein-Protein Interactions in Alpha-Synuclein\nBiogenesis: New Potential Targets in Parkinson\u2019s Disease","volume":"12","author":"Hernandez","year":"2020","journal-title":"Front. Aging Neurosci."},{"issue":"16","key":"2026102207420637200_cit4","doi-asserted-by":"publisher","first-page":"13131","DOI":"10.1021\/jacs.4c13473","article-title":"Local Ionic Conditions\nModulate the Aggregation Propensity and Influence the Structural Polymorphism\nof alpha-Synuclein","volume":"147","author":"Zacharopoulou","year":"2025","journal-title":"J. Am. Chem. Soc."},{"issue":"3","key":"2026102207420637200_cit5","doi-asserted-by":"publisher","first-page":"a024091","DOI":"10.1101\/cshperspect.a024091","article-title":"Cell Biology\nand Pathophysiology\nof alpha-Synuclein","volume":"8","author":"Burre","year":"2018","journal-title":"Cold Spring Harbor Perspect.\nMed."},{"issue":"1","key":"2026102207420637200_cit6","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s13024-019-0329-1","article-title":"Alpha-synuclein\nstructure and Parkinson\u2019s\ndisease - lessons and emerging principles","volume":"14","author":"Meade","year":"2019","journal-title":"Mol.\nNeurodegener."},{"issue":"1","key":"2026102207420637200_cit7","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1039\/C4MB00356J","article-title":"Alpha-synuclein oligomers\nand fibrils originate in two distinct conformer\npools: a small angle X-ray scattering and ensemble optimization modelling\nstudy","volume":"11","author":"Curtain","year":"2014","journal-title":"Mol. BioSyst."},{"issue":"12","key":"2026102207420637200_cit8","doi-asserted-by":"publisher","first-page":"7804","DOI":"10.1074\/jbc.M114.598607","article-title":"Familial Parkinson\ndisease-associated mutations alter the site-specific microenvironment\nand dynamics of alpha-synuclein","volume":"290","author":"Sahay","year":"2015","journal-title":"J. Biol. Chem."},{"issue":"38","key":"2026102207420637200_cit9","doi-asserted-by":"publisher","first-page":"13997","DOI":"10.1073\/pnas.0606236103","article-title":"A molecular\nmechanism for osmolyte-induced\nprotein stability","volume":"103","author":"Street","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026102207420637200_cit10","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1146\/annurev.biochem.75.101304.123901","article-title":"Protein misfolding,\nfunctional amyloid, and human disease","volume":"75","author":"Chiti","year":"2006","journal-title":"Annu.\nRev. 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Mass Spectrom."},{"issue":"2","key":"2026102207420637200_cit29","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1038\/nchem.945","article-title":"Ion mobility-mass\nspectrometry reveals a conformational conversion from random assembly\nto beta-sheet in amyloid fibril formation","volume":"3","author":"Bleiholder","year":"2011","journal-title":"Nat.\nChem."},{"key":"2026102207420637200_cit30","doi-asserted-by":"publisher","first-page":"20555","DOI":"10.1021\/jacs.6c01293","article-title":"Mechanism\nof Aggregation\nof the NACore of alpha-Synuclein: Stable Oligomer Formation Competes\nwith Fibril Formation with Implications for the Etiology of Parkinson\u2019s\nDisease","volume":"148","author":"Jin","year":"2026","journal-title":"J. Am. Chem. 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Med.\nChem."},{"issue":"6","key":"2026102207420637200_cit40","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1021\/acs.biochem.5c00782","article-title":"The Power\nof Protein Dynamics in Binding and Allostery","volume":"65","author":"Lee","year":"2026","journal-title":"Biochemistry"},{"key":"2026102207420637200_cit41","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.ijms.2017.09.014","article-title":"Conformational\nLandscapes of Ubiquitin,\nCytochrome c, and Myoglobin: Uniform Field Ion Mobility Measurements\nin Helium and Nitrogen Drift Gas","volume":"427","author":"May","year":"2018","journal-title":"Int. J. Mass\nSpectrom."},{"issue":"17","key":"2026102207420637200_cit42","doi-asserted-by":"publisher","first-page":"9048","DOI":"10.1021\/acs.analchem.7b01729","article-title":"An Interlaboratory\nEvaluation of Drift Tube Ion Mobility-Mass Spectrometry Collision\nCross Section Measurements","volume":"89","author":"Stow","year":"2017","journal-title":"Anal. 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