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Notwithstanding sensitivity, this information can, in principle, be obtained for any protein present with no requirement for a priori knowledge of protein identity. To date, native ambient mass spectrometry has primarily made use of the liquid extraction surface analysis (LESA) sampling technique. Here, we address a fundamental question: Are the protein structures observed following native liquid extraction surface analysis representative of the protein structures within the substrate, or does the extraction process facilitate refolding (or unfolding)? Specifically, our aim was to determine whether protein\u2013ligand complexes observed following LESA are indicative of complexes present in the substrate, or an artifact of the sampling process. The systems investigated were myoglobin and its noncovalently bound heme cofactor, and the Zn-binding protein carbonic anhydrase and its binding with ethoxzolamide. Charge state distributions, drift time profiles, and collision cross sections were determined by liquid extraction surface analysis ion mobility mass spectrometry of native and denatured proteins and compared with those obtained by direct infusion electrospray. The results show that it was not possible to refold denatured proteins with concomitant ligand binding (neither heme, zinc, nor ethoxzolamide) simply by use of native-like LESA solvents. That is, protein\u2013ligand complexes were only observed by LESA MS when present in the substrate.<\/jats:p>","DOI":"10.1021\/acs.analchem.9b02075","type":"journal-article","created":{"date-parts":[[2019,9,6]],"date-time":"2019-09-06T13:23:12Z","timestamp":1567776192000},"page":"12246-12254","source":"Crossref","is-referenced-by-count":10,"title":["Probing the Fundamentals of Native Liquid Extraction\nSurface Analysis Mass Spectrometry of Proteins: Can Proteins Refold\nduring Extraction?"],"prefix":"10.1021","volume":"91","author":[{"given":"Eva","family":"Illes-Toth","sequence":"first","affiliation":[{"name":"University of Birmingham , , , ,","place":["Birmingham, U.K., B15 2TT"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4590-9384","authenticated-orcid":true,"given":"Helen J.","family":"Cooper","sequence":"additional","affiliation":[{"name":"University of Birmingham , , , ,","place":["Birmingham, U.K., B15 2TT"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2019,9,6]]},"reference":[{"issue":"3","key":"2026090211320413100_cit1","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1002\/jms.1709","article-title":"Fully automated\nliquid extraction-based surface sampling and ionization using a chip-based\nrobotic nanoelectrospray platform","volume":"45","author":"Kertesz","year":"2010","journal-title":"J. Mass Spectrom."},{"issue":"11","key":"2026090211320413100_cit2","doi-asserted-by":"publisher","first-page":"1420","DOI":"10.1002\/jms.3068","article-title":"Analysis\nof chloroquine and metabolites directly from whole-body animal tissue\nsections by liquid extraction surface analysis (LESA) and tandem mass\nspectrometry","volume":"47","author":"Parson","year":"2012","journal-title":"J. Mass Spectrom."},{"issue":"19","key":"2026090211320413100_cit3","doi-asserted-by":"publisher","first-page":"10146","DOI":"10.1021\/acs.analchem.5b02998","article-title":"Mapping\ndrug distribution in brain tissue using liquid extraction surface\nanalysis mass spectrometry imaging","volume":"87","author":"Swales","year":"2015","journal-title":"Anal. Chem."},{"issue":"4","key":"2026090211320413100_cit4","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1002\/rcm.6116","article-title":"Direct\ndetection of additives and degradation products from polymers by liquid\nextraction surface analysis employing chip-based nanospray mass spectrometry","volume":"26","author":"Paine","year":"2012","journal-title":"Rapid Commun. Mass Spectrom."},{"issue":"7","key":"2026090211320413100_cit5","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1111\/papr.12688","article-title":"Unique Intradural\nInflammatory Mass Containing Precipitated Morphine: Confirmatory Analysis\nby LESA-MS and MALDI-MS","volume":"18","author":"Kim","year":"2018","journal-title":"Pain Pract"},{"issue":"20","key":"2026090211320413100_cit6","doi-asserted-by":"publisher","first-page":"2477","DOI":"10.1002\/rcm.6365","article-title":"Direct mass spectrometric screening\nof antibiotics from bacterial surfaces using liquid extraction surface\nanalysis","volume":"26","author":"Kai","year":"2012","journal-title":"Rapid Commun. Mass Spectrom."},{"key":"2026090211320413100_cit7","doi-asserted-by":"publisher","first-page":"273","DOI":"10.2147\/IJN.S151475","article-title":"Lactoferrin-modified rotigotine nanoparticles\nfor enhanced nose-to-brain delivery: LESA-MS\/MS-based drug biodistribution,\npharmacodynamics, and neuroprotective effects","volume":"13","author":"Yan","year":"2018","journal-title":"Int. J. Nanomed."},{"issue":"3","key":"2026090211320413100_cit8","doi-asserted-by":"publisher","first-page":"150","DOI":"10.2533\/chimia.2014.150","article-title":"Liquid extraction surface analysis\n(LESA) of hydrophobic TLC plates coupled to chip-based nanoelectrospray\nhigh-resolution mass spectrometry","volume":"68","author":"Himmelsbach","year":"2014","journal-title":"Chimia"},{"issue":"9","key":"2026090211320413100_cit9","doi-asserted-by":"publisher","first-page":"5161","DOI":"10.1021\/acs.analchem.7b01097","article-title":"Liquid Extraction Surface Analysis Mass Spectrometry\nMethod for Identifying the Presence and Severity of Nonalcoholic Fatty\nLiver Disease","volume":"89","author":"Hall","year":"2017","journal-title":"Anal. Chem."},{"issue":"20","key":"2026090211320413100_cit10","doi-asserted-by":"publisher","first-page":"10257","DOI":"10.1021\/ac502449w","article-title":"Rapid detection of peptide markers\nfor authentication purposes in raw and cooked meat using ambient liquid\nextraction surface analysis mass spectrometry","volume":"86","author":"Montowska","year":"2014","journal-title":"Anal. Chem."},{"issue":"5","key":"2026090211320413100_cit11","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1002\/rcm.8042","article-title":"Protein\nidentification in imaging mass spectrometry through spatially targeted\nliquid micro-extractions","volume":"32","author":"Ryan","year":"2018","journal-title":"Rapid Commun. Mass\nSpectrom."},{"issue":"20","key":"2026090211320413100_cit12","doi-asserted-by":"publisher","first-page":"11143","DOI":"10.1021\/acs.analchem.7b03512","article-title":"Integration of Ion Mobility MS(E)\nafter Fully Automated, Online, High-Resolution Liquid Extraction Surface\nAnalysis Micro-Liquid Chromatography","volume":"89","author":"Lamont","year":"2017","journal-title":"Anal.\nChem."},{"issue":"6","key":"2026090211320413100_cit13","doi-asserted-by":"publisher","first-page":"2265","DOI":"10.1021\/ac1030804","article-title":"Hemoglobin variant analysis via direct\nsurface sampling of dried blood spots coupled with high-resolution\nmass spectrometry","volume":"83","author":"Edwards","year":"2011","journal-title":"Anal. Chem."},{"issue":"8","key":"2026090211320413100_cit14","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1007\/s13361-013-0658-1","article-title":"Dried blood spot proteomics: surface extraction of\nendogenous proteins coupled with automated sample preparation and\nmass spectrometry analysis","volume":"24","author":"Martin","year":"2013","journal-title":"J. Am. Soc. Mass\nSpectrom."},{"issue":"8","key":"2026090211320413100_cit15","doi-asserted-by":"publisher","first-page":"1320","DOI":"10.1007\/s13361-015-1152-8","article-title":"Native\nLiquid Extraction Surface Analysis Mass Spectrometry: Analysis of\nNoncovalent Protein Complexes Directly from Dried Substrates","volume":"26","author":"Martin","year":"2015","journal-title":"J. Am. Soc. Mass Spectrom."},{"issue":"21","key":"2026090211320413100_cit16","doi-asserted-by":"publisher","first-page":"10504","DOI":"10.1021\/ac503349d","article-title":"Direct\nanalysis of intact proteins from Escherichia coli colonies by liquid\nextraction surface analysis mass spectrometry","volume":"86","author":"Randall","year":"2014","journal-title":"Anal. Chem."},{"issue":"1","key":"2026090211320413100_cit17","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1021\/acs.analchem.5b03993","article-title":"Direct Tissue Profiling of Protein Complexes: Toward\nNative Mass Spectrometry Imaging","volume":"88","author":"Griffiths","year":"2016","journal-title":"Anal. Chem."},{"issue":"10","key":"2026090211320413100_cit18","doi-asserted-by":"publisher","first-page":"2066","DOI":"10.1007\/s13361-017-1718-8","article-title":"Top-Down\nLESA Mass Spectrometry Protein Analysis of Gram-Positive and Gram-Negative\nBacteria","volume":"28","author":"Kocurek","year":"2017","journal-title":"J. Am. Soc. Mass Spectrom."},{"key":"2026090211320413100_cit19","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.ijms.2016.09.011","article-title":"Liquid extraction surface analysis\nfor native mass spectrometry: Protein complexes and ligand binding","volume":"420","author":"Mikhailov","year":"2017","journal-title":"Int. J. Mass Spectrom."},{"key":"2026090211320413100_cit20","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.ijms.2017.10.009","article-title":"Native mass spectrometry\nimaging of intact proteins and protein complexes in thin tissue sections","volume":"437","author":"Griffiths","year":"2019","journal-title":"Int. J. Mass Spectrom."},{"issue":"3","key":"2026090211320413100_cit21","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1255\/ejms.1058","article-title":"Multi-step evolution\nof protein conformation on electrospray into the gas phase","volume":"16","author":"McLafferty","year":"2010","journal-title":"Eur. J. 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Chem."},{"issue":"2","key":"2026090211320413100_cit31","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1255\/ejms.947","article-title":"Deciphering\ndrift time measurements from travelling wave ion mobility spectrometry-mass\nspectrometry studies","volume":"15","author":"Smith","year":"2009","journal-title":"Eur. J. Mass Spectrom."},{"issue":"7","key":"2026090211320413100_cit32","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1007\/s13361-019-02178-7","article-title":"Cryo-LESA\nMass Spectrometry\u2500a Step Towards Truly Native Surface Sampling\nof Proteins","volume":"30","author":"Yan","year":"2019","journal-title":"J. Am. Soc. Mass Spectrom."},{"issue":"42","key":"2026090211320413100_cit33","doi-asserted-by":"publisher","first-page":"12266","DOI":"10.1021\/jp206867a","article-title":"Structural stability from solution to the gas phase:\nnative solution structure of ubiquitin survives analysis in a solvent-free\nion mobility-mass spectrometry environment","volume":"115","author":"Wyttenbach","year":"2011","journal-title":"J. Phys. Chem. B"},{"issue":"13","key":"2026090211320413100_cit34","doi-asserted-by":"publisher","first-page":"3498","DOI":"10.1021\/jp4097327","article-title":"Evidence for two\nnew solution states of ubiquitin by IMS-MS analysis","volume":"118","author":"Shi","year":"2014","journal-title":"J. Phys. Chem. B"},{"issue":"12","key":"2026090211320413100_cit35","doi-asserted-by":"publisher","first-page":"2000","DOI":"10.1007\/s13361-014-0834-y","article-title":"Solution dependence of the collisional\nactivation of ubiquitin [M + 7H](7+) ions","volume":"25","author":"Shi","year":"2014","journal-title":"J.\nAm. Soc. Mass Spectrom."},{"issue":"3","key":"2026090211320413100_cit36","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1002\/mas.21585","article-title":"Recommendations for reporting ion\nmobility Mass Spectrometry measurements","volume":"38","author":"Gabelica","year":"2019","journal-title":"Mass\nSpectrom. Rev."},{"issue":"13","key":"2026090211320413100_cit37","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera--a visualization system\nfor exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput.\nChem."},{"issue":"4","key":"2026090211320413100_cit38","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1007\/s13361-014-1067-9","article-title":"Kinetic intermediates of holo- and apo-myoglobin studied\nusing HDX-TIMS-MS and molecular dynamic simulations","volume":"26","author":"Schenk","year":"2015","journal-title":"J. Am. Soc. Mass Spectrom."},{"issue":"45","key":"2026090211320413100_cit39","doi-asserted-by":"publisher","first-page":"14173","DOI":"10.1002\/anie.201606029","article-title":"Retention\nof Native Protein Structures in the Absence of Solvent: A Coupled\nIon Mobility and Spectroscopic Study","volume":"55","author":"Seo","year":"2016","journal-title":"Angew.\nChem., Int. Ed."},{"key":"2026090211320413100_cit40","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.ijms.2017.09.014","article-title":"Conformational\nLandscapes of Ubiquitin, Cytochrome c, and Myoglobin: Uniform Field\nIon Mobility Measurements in Helium and Nitrogen Drift Gas","volume":"427","author":"May","year":"2018","journal-title":"Int. J. Mass Spectrom."},{"issue":"4","key":"2026090211320413100_cit41","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1016\/S0022-2836(05)80270-0","article-title":"High-resolution study of the three-dimensional\nstructure of horse heart metmyoglobin","volume":"213","author":"Evans","year":"1990","journal-title":"J. Mol.\nBiol."},{"issue":"1\u20133","key":"2026090211320413100_cit42","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/0301-4622(90)88024-M","article-title":"Horse heart myoglobin reconstituted with a symmetrical\nheme. A circular dichroism study","volume":"37","author":"Santucci","year":"1990","journal-title":"Biophys. Chem."},{"issue":"13","key":"2026090211320413100_cit43","doi-asserted-by":"crossref","first-page":"4623","DOI":"10.1016\/S0021-9258(19)43709-5","article-title":"The equilibrium unfolding parameters of horse and sperm whale myoglobin.\nEffects of guanidine hydrochloride, urea, and acid","volume":"248","author":"Puett","year":"1973","journal-title":"J. Biol. Chem."},{"issue":"5","key":"2026090211320413100_cit44","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1006\/jmbi.1994.1257","article-title":"Molecular mechanisms\nof acid denaturation. The role of histidine residues in the partial\nunfolding of apomyoglobin","volume":"237","author":"Barrick","year":"1994","journal-title":"J. Mol. Biol."},{"issue":"20","key":"2026090211320413100_cit45","doi-asserted-by":"publisher","first-page":"4763","DOI":"10.1021\/ac010713f","article-title":"Detection of multiple protein conformational ensembles\nin solution via deconvolution of charge-state distributions in ESI\nMS","volume":"73","author":"Dobo","year":"2001","journal-title":"Anal. Chem."},{"issue":"2","key":"2026090211320413100_cit46","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1042\/bj1590371","article-title":"The kinetics and mechanism of the\nrecombination reaction between apomyoglobin and haemin","volume":"159","author":"Adams","year":"1976","journal-title":"Biochem. J."},{"issue":"19","key":"2026090211320413100_cit47","doi-asserted-by":"publisher","first-page":"4154","DOI":"10.1021\/ac9904664","article-title":"Reconstitution of acid-denatured\nholomyoglobin studied by time-resolved electrospray ionization mass\nspectrometry","volume":"71","author":"Lee","year":"1999","journal-title":"Anal. Chem."},{"issue":"8","key":"2026090211320413100_cit48","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1016\/1044-0305(93)85028-V","article-title":"Stepwise refolding\nof acid-denatured myoglobin: evidence from electrospray mass spectrometry","volume":"4","author":"Feng","year":"1993","journal-title":"J. Am. Soc. Mass Spectrom."},{"issue":"10","key":"2026090211320413100_cit49","doi-asserted-by":"publisher","first-page":"3325","DOI":"10.1073\/pnas.0400157101","article-title":"Water and proteins:\na love-hate relationship","volume":"101","author":"Levy","year":"2004","journal-title":"Proc. Natl. Acad.\nSci. U. S. A."},{"issue":"17","key":"2026090211320413100_cit50","doi-asserted-by":"publisher","first-page":"5127","DOI":"10.1021\/bi002255v","article-title":"Structures of apomyoglobin\u2019s various acid-destabilized\nforms","volume":"40","author":"Gilmanshin","year":"2001","journal-title":"Biochemistry"},{"issue":"17","key":"2026090211320413100_cit51","doi-asserted-by":"publisher","first-page":"5137","DOI":"10.1021\/bi002256n","article-title":"Core Formation in\nApomyoglobin: Probing the Upper Reaches of the Folding Energy Landscape","volume":"40","author":"Gulotta","year":"2001","journal-title":"Biochemistry"},{"issue":"1","key":"2026090211320413100_cit52","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/S1359-0278(98)00005-4","article-title":"Discrete intermediates\nversus molten globule models for protein folding: characterization\nof partially folded intermediates of apomyoglobin","volume":"3","author":"Fink","year":"1998","journal-title":"Folding Des."},{"issue":"9","key":"2026090211320413100_cit53","doi-asserted-by":"publisher","first-page":"2505","DOI":"10.1073\/pnas.70.9.2505","article-title":"The catalytic mechanism of carbonic\nanhydrase","volume":"70","author":"Lindskog","year":"1973","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"Pt 4","key":"2026090211320413100_cit54","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1107\/S0907444904003166","article-title":"Structure of bovine\ncarbonic anhydrase II at 1.95 A resolution","volume":"60","author":"Saito","year":"2004","journal-title":"Acta Crystallogr., Sect. D: Biol. Crystallogr."},{"issue":"1","key":"2026090211320413100_cit55","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1002\/prot.340160104","article-title":"Refined structure of\nbovine carbonic anhydrase III at 2.0 A resolution","volume":"16","author":"Eriksson","year":"1993","journal-title":"Proteins: Struct., Funct., Genet."},{"issue":"4","key":"2026090211320413100_cit56","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1002\/jmr.951","article-title":"Label-free determination of protein-ligand binding\nconstants using mass spectrometry and validation using surface plasmon\nresonance and isothermal titration calorimetry","volume":"22","author":"Jecklin","year":"2009","journal-title":"J. Mol. Recognit."},{"issue":"2","key":"2026090211320413100_cit57","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1021\/acscentsci.8b00787","article-title":"Nanoscale Ion Emitters in Native Mass Spectrometry\nfor Measuring Ligand-Protein Binding Affinities","volume":"5","author":"Nguyen","year":"2019","journal-title":"ACS Cent. Sci."},{"issue":"4","key":"2026090211320413100_cit58","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1177\/1087057108315739","article-title":"Direct screening of natural product\nextracts using mass spectrometry","volume":"13","author":"Vu","year":"2008","journal-title":"J. Biomol.\nScreening"},{"issue":"7","key":"2026090211320413100_cit59","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1177\/1087057106289403","article-title":"Inhibition profiling of human carbonic\nanhydrase II by high-throughput screening of structurally diverse,\nbiologically active compounds","volume":"11","author":"Iyer","year":"2006","journal-title":"J. Biomol. Screening"},{"issue":"3","key":"2026090211320413100_cit60","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/S0026-895X(25)10497-5","article-title":"The effect of temperature on the binding of sulfonamides\nto carbonic anhydrase isoenzymes I, II, and IV","volume":"48","author":"Conroy","year":"1995","journal-title":"Mol. Pharmacol."},{"issue":"8","key":"2026090211320413100_cit61","doi-asserted-by":"publisher","first-page":"2669","DOI":"10.1016\/j.bmcl.2008.03.023","article-title":"Carbonic anhydrase\ninhibitors: the X-ray crystal structure of ethoxzolamide complexed\nto human isoform II reveals the importance of thr200 and gln92 for\nobtaining tight-binding inhibitors","volume":"18","author":"Di Fiore","year":"2008","journal-title":"Bioorg.\nMed. Chem. 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