{"id":"https://openalex.org/W7224679960","doi":"https://doi.org/10.64898/2026.10.28.762400","title":"Multi-Ensemble Reweighting Enables Structural Interpretation of Differential HDX-MS","display_name":"Multi-Ensemble Reweighting Enables Structural Interpretation of Differential HDX-MS","publication_year":2026,"publication_date":"2026-10-29","ids":{"openalex":"https://openalex.org/W7224679960","doi":"https://doi.org/10.64898/2026.10.28.762400"},"language":"en","primary_location":{"id":"doi:10.64898/2026.10.28.762400","doi":"https://doi.org/10.64898/2026.10.28.762400","is_oa":true,"landing_page_url":"https://doi.org/10.64898/2026.10.28.762400","pdf_url":"https://www.biorxiv.org/content/biorxiv/early/2026/10/29/2026.10.28.762400.full.pdf","source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"},"volume":null,"type":"preprint","indexed_in":["crossref"],"open_access":{"is_oa":true,"oa_status":"green","oa_url":"https://www.biorxiv.org/content/biorxiv/early/2026/10/29/2026.10.28.762400.full.pdf","any_repository_has_fulltext":true},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5050733346","display_name":"Sandra Byju","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I204308271","display_name":"Medical College of Wisconsin","ror":"https://ror.org/00qqv6244","country_code":"US","type":"education","lineage":["https://openalex.org/I204308271"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Sandra Byju","raw_affiliation_strings":["Department of Biophysics and Data Science Institute, Medical College of Wisconsin, Milwaukee, WI 53226-3548, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Department of Biophysics and Data Science Institute, Medical College of Wisconsin, Milwaukee, WI 53226-3548, USA","institution_ids":["https://openalex.org/I204308271"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5013107480","display_name":"Vincent M. Lowe","orcid":"https://orcid.org/0000-0003-3651-8461","observed_orcids":["https://orcid.org/0000-0003-3651-8461"]},"institutions":[{"id":"https://openalex.org/I126744593","display_name":"University of Maryland, Baltimore","ror":"https://ror.org/04rq5mt64","country_code":"US","type":"education","lineage":["https://openalex.org/I126744593"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Vincent Lowe","raw_affiliation_strings":["Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, 21201, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, 21201, USA","institution_ids":["https://openalex.org/I126744593"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5024035683","display_name":"Daniel Joseph Deredge","orcid":"https://orcid.org/0000-0002-6897-6523","observed_orcids":["https://orcid.org/0000-0002-6897-6523"]},"institutions":[{"id":"https://openalex.org/I126744593","display_name":"University of Maryland, Baltimore","ror":"https://ror.org/04rq5mt64","country_code":"US","type":"education","lineage":["https://openalex.org/I126744593"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Daniel J. Deredge","raw_affiliation_strings":["Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, 21201, USA"],"raw_orcid":"https://orcid.org/0000-0002-6897-6523","affiliations":[{"raw_affiliation_string":"Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, 21201, USA","institution_ids":["https://openalex.org/I126744593"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5066819680","display_name":"Fabrizio Marinelli","orcid":"https://orcid.org/0000-0003-0044-6718","observed_orcids":["https://orcid.org/0000-0003-0044-6718"]},"institutions":[{"id":"https://openalex.org/I204308271","display_name":"Medical College of Wisconsin","ror":"https://ror.org/00qqv6244","country_code":"US","type":"education","lineage":["https://openalex.org/I204308271"]},{"id":"https://openalex.org/I4210117001","display_name":"Versiti Blood Center of Wisconsin","ror":"https://ror.org/02sjnfb25","country_code":"US","type":"healthcare","lineage":["https://openalex.org/I4210117001"]},{"id":"https://openalex.org/I4405279567","display_name":"Versiti Blood Research Institute Foundation","ror":"https://ror.org/01pavyk18","country_code":"US","type":"nonprofit","lineage":["https://openalex.org/I4405279567"]}],"countries":["US"],"is_corresponding":true,"raw_author_name":"Fabrizio Marinelli","raw_affiliation_strings":["Department of Biophysics and Data Science Institute, Medical College of Wisconsin, Milwaukee, WI 53226-3548, USA","Versiti Blood Research Institute. Milwaukee, WI 53226-3548, USA"],"raw_orcid":"https://orcid.org/0000-0003-0044-6718","affiliations":[{"raw_affiliation_string":"Department of Biophysics and Data Science Institute, Medical College of Wisconsin, Milwaukee, WI 53226-3548, USA","institution_ids":["https://openalex.org/I204308271"]},{"raw_affiliation_string":"Versiti Blood Research Institute. Milwaukee, WI 53226-3548, USA","institution_ids":["https://openalex.org/I4210117001","https://openalex.org/I4405279567"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":4,"corresponding_author_ids":["https://openalex.org/A5066819680"],"corresponding_institution_ids":["https://openalex.org/I204308271","https://openalex.org/I4210117001","https://openalex.org/I4405279567"],"apc_list":null,"apc_paid":null,"fwci":null,"has_fulltext":true,"cited_by_count":0,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T10683","display_name":"Mass Spectrometry Techniques and Applications","score":0.9301999807357788,"subfield":{"id":"https://openalex.org/subfields/1607","display_name":"Spectroscopy"},"field":{"id":"https://openalex.org/fields/16","display_name":"Chemistry"},"domain":{"id":"https://openalex.org/domains/3","display_name":"Physical Sciences"}},"topics":[{"id":"https://openalex.org/T10683","display_name":"Mass Spectrometry Techniques and Applications","score":0.9301999807357788,"subfield":{"id":"https://openalex.org/subfields/1607","display_name":"Spectroscopy"},"field":{"id":"https://openalex.org/fields/16","display_name":"Chemistry"},"domain":{"id":"https://openalex.org/domains/3","display_name":"Physical Sciences"}},{"id":"https://openalex.org/T10044","display_name":"Protein Structure and Dynamics","score":0.06360000371932983,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T11162","display_name":"Enzyme Structure and Function","score":0.0027000000700354576,"subfield":{"id":"https://openalex.org/subfields/2505","display_name":"Materials Chemistry"},"field":{"id":"https://openalex.org/fields/25","display_name":"Materials Science"},"domain":{"id":"https://openalex.org/domains/3","display_name":"Physical Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/protein-conformational-change","display_name":"protein conformational change","score":0.6710000038146973},{"id":"https://openalex.org/keywords/leut","display_name":"LeuT","score":0.6959999799728394},{"id":"https://openalex.org/keywords/integrative-structural-modeling","display_name":"integrative structural modeling","score":0.7229999899864197}],"concepts":[{"id":"https://openalex.org/C55037315","wikidata":"https://www.wikidata.org/wiki/Q5421151","display_name":"Experimental data","level":2,"score":0.620199978351593},{"id":"https://openalex.org/C527412718","wikidata":"https://www.wikidata.org/wiki/Q855395","display_name":"Interpretation (philosophy)","level":2,"score":0.5605999827384949},{"id":"https://openalex.org/C121864883","wikidata":"https://www.wikidata.org/wiki/Q677916","display_name":"Statistical physics","level":1,"score":0.5418000221252441},{"id":"https://openalex.org/C41008148","wikidata":"https://www.wikidata.org/wiki/Q21198","display_name":"Computer science","level":0,"score":0.5189999938011169},{"id":"https://openalex.org/C58364064","wikidata":"https://www.wikidata.org/wiki/Q102296","display_name":"Deuterium","level":2,"score":0.4846000075340271},{"id":"https://openalex.org/C11413529","wikidata":"https://www.wikidata.org/wiki/Q8366","display_name":"Algorithm","level":1,"score":0.48069998621940613},{"id":"https://openalex.org/C186060115","wikidata":"https://www.wikidata.org/wiki/Q30336093","display_name":"Biological system","level":1,"score":0.4731000065803528},{"id":"https://openalex.org/C93226319","wikidata":"https://www.wikidata.org/wiki/Q193137","display_name":"Differential (mechanical device)","level":2,"score":0.45489999651908875},{"id":"https://openalex.org/C2908647359","wikidata":"https://www.wikidata.org/wiki/Q2625603","display_name":"Population","level":2,"score":0.45080000162124634},{"id":"https://openalex.org/C167569220","wikidata":"https://www.wikidata.org/wiki/Q5954985","display_name":"Hydrogen\u2013deuterium exchange","level":3,"score":0.4284000098705292},{"id":"https://openalex.org/C59593255","wikidata":"https://www.wikidata.org/wiki/Q901663","display_name":"Molecular dynamics","level":2,"score":0.38659998774528503},{"id":"https://openalex.org/C198531522","wikidata":"https://www.wikidata.org/wiki/Q485146","display_name":"Sample (material)","level":2,"score":0.3449999988079071},{"id":"https://openalex.org/C3019813237","wikidata":"https://www.wikidata.org/wiki/Q65089264","display_name":"Model validation","level":2,"score":0.3059000074863434},{"id":"https://openalex.org/C185592680","wikidata":"https://www.wikidata.org/wiki/Q2329","display_name":"Chemistry","level":0,"score":0.29030001163482666},{"id":"https://openalex.org/C124101348","wikidata":"https://www.wikidata.org/wiki/Q172491","display_name":"Data mining","level":1,"score":0.28040000796318054},{"id":"https://openalex.org/C2780009758","wikidata":"https://www.wikidata.org/wiki/Q6804172","display_name":"Measure (data warehouse)","level":2,"score":0.2800000011920929},{"id":"https://openalex.org/C204323151","wikidata":"https://www.wikidata.org/wiki/Q905424","display_name":"Range (aeronautics)","level":2,"score":0.2768999934196472},{"id":"https://openalex.org/C160920958","wikidata":"https://www.wikidata.org/wiki/Q7662746","display_name":"Synthetic data","level":2,"score":0.26499998569488525},{"id":"https://openalex.org/C2775981520","wikidata":"https://www.wikidata.org/wiki/Q17156992","display_name":"Protein dynamics","level":3,"score":0.25999999046325684},{"id":"https://openalex.org/C121332964","wikidata":"https://www.wikidata.org/wiki/Q413","display_name":"Physics","level":0,"score":0.25920000672340393},{"id":"https://openalex.org/C145912823","wikidata":"https://www.wikidata.org/wiki/Q113558","display_name":"Dynamics (music)","level":2,"score":0.2565000057220459}],"mesh":[],"locations_count":1,"locations":[{"id":"doi:10.64898/2026.10.28.762400","doi":"https://doi.org/10.64898/2026.10.28.762400","is_oa":true,"landing_page_url":"https://doi.org/10.64898/2026.10.28.762400","pdf_url":"https://www.biorxiv.org/content/biorxiv/early/2026/10/29/2026.10.28.762400.full.pdf","source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"}],"best_oa_location":{"id":"doi:10.64898/2026.10.28.762400","doi":"https://doi.org/10.64898/2026.10.28.762400","is_oa":true,"landing_page_url":"https://doi.org/10.64898/2026.10.28.762400","pdf_url":"https://www.biorxiv.org/content/biorxiv/early/2026/10/29/2026.10.28.762400.full.pdf","source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"},"sustainable_development_goals":[],"study_designs":[],"awards":[],"funders":[{"id":"https://openalex.org/F4320310914","display_name":"Medical College of Wisconsin","ror":"https://ror.org/00qqv6244"}],"has_content":{"grobid_xml":true,"pdf":true},"content_urls":{"pdf":"https://content.openalex.org/works/W7224679960.pdf","grobid_xml":"https://content.openalex.org/works/W7224679960.grobid-xml"},"referenced_works_count":0,"referenced_works":[],"related_works":["https://openalex.org/W3005401130","https://openalex.org/W3006470483","https://openalex.org/W4211250080","https://openalex.org/W4211066195","https://openalex.org/W3131604484","https://openalex.org/W4319919518","https://openalex.org/W4206928854","https://openalex.org/W4319916247","https://openalex.org/W4211193593","https://openalex.org/W4407493651"],"abstract_inverted_index":{"ABSTRACT":[0],"Hydrogen\u2013deuterium":[1],"exchange":[2],"mass":[3],"spectrometry":[4],"(HDX-MS)":[5],"provides":[6],"information":[7],"on":[8],"protein":[9],"structure":[10],"and":[11,32,41,63,84,127,142,204],"dynamics":[12],"that":[13,97],"complements":[14],"high-resolution":[15],"structural":[16,54,176,205],"methods.":[17,70],"Most":[18],"HDX-MS":[19,123,218],"studies":[20],"are":[21,80],"differential,":[22],"comparing":[23],"deuterium":[24,58,102],"uptake":[25,51],"between":[26],"biological":[27],"states,":[28],"such":[29],"as":[30,53],"ligand-bound":[31],"unbound":[33],"forms.":[34],"Integrating":[35],"these":[36,196],"data":[37,124],"with":[38,139,146],"molecular":[39],"modeling":[40,210],"simulations":[42],"through":[43],"maximum-entropy":[44],"ensemble":[45],"reweighting":[46,95,116,131,145,192],"enables":[47],"quantitative":[48,208],"interpretation":[49],"of":[50,217],"differences":[52],"population":[55],"shifts.":[56],"However,":[57],"loss":[59,103],"during":[60],"sample":[61],"preparation":[62],"analysis,":[64],"often":[65,85],"exceeding":[66],"50%,":[67],"limits":[68],"existing":[69],"Although":[71],"fully":[72],"deuterated":[73],"controls":[74],"enable":[75],"approximate":[76],"experimental":[77,107,122],"correction,":[78],"they":[79],"difficult":[81],"to":[82,114,121,154,162,191,200,214],"obtain":[83],"omitted":[86],"from":[87,211],"differential":[88],"studies.":[89],"Here,":[90],"we":[91],"introduce":[92],"a":[93],"multi-ensemble":[94,130],"methodology":[96],"accounts":[98],"for":[99,125],"shared,":[100],"peptide-dependent":[101],"without":[104],"requiring":[105],"its":[106,152],"characterization.":[108],"Synthetic":[109],"benchmarks":[110],"demonstrated":[111],"accuracy":[112],"comparable":[113],"conventional":[115,144],"using":[117],"loss-corrected":[118],"data.":[119,148],"Applied":[120],"wild-type":[126],"Y268A":[128],"LeuT,":[129],"captures":[132],"the":[133,166,179,185,215],"transporter":[134],"alternating-access":[135,187],"transition,":[136,188],"improves":[137],"agreement":[138],"X-ray":[140],"structures,":[141],"outperforms":[143],"deuterium-loss-corrected":[147],"We":[149],"then":[150],"assessed":[151],"ability":[153],"resolve":[155],"subtler":[156],"conformational":[157,202],"changes":[158],"by":[159],"applying":[160],"it":[161],"substrate-induced":[163],"occlusion":[164],"in":[165],"Na":[167],"+":[168],"/Ca":[169],"2+":[170],"exchanger":[171],"NCX_Mj,":[172],"recovering":[173],"experimentally":[174],"supported":[175],"changes.":[177],"Finally,":[178],"framework":[180],"ranked":[181],"AlphaFold3-derived":[182],"ensembles":[183],"along":[184],"NCX_Mj":[186],"performing":[189],"comparably":[190],"simulation-derived":[193],"ensembles.":[194],"Together,":[195],"applications":[197],"demonstrate":[198],"applicability":[199],"diverse":[201],"transitions":[203],"inputs,":[206],"extending":[207],"integrative":[209],"approximately":[212],"one-quarter":[213],"majority":[216],"datasets":[219],"while":[220],"improving":[221],"accuracy.":[222]},"counts_by_year":[],"updated_date":"2026-11-05T12:25:35.769452","created_date":"2026-10-30T00:00:00"}