{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:38:58Z","timestamp":1792607938665,"version":"4.5.0"},"reference-count":66,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01-AI116525"],"award-info":[{"award-number":["R01-AI116525"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Tuberculosis (TB), caused by\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (\n                    <jats:italic>Mtb<\/jats:italic>\n                    ), remains a global health crisis, further complicated by increasing drug resistance. The mycobacterial membrane protein MmpL3, which is essential for transporting cell wall precursors such as trehalose monomycolate (TMM), is a promising therapeutic target. However, the mechanistic link between proton-driven dynamics and substrate transport in MmpL3 is not fully understood. In this study, we use molecular dynamics simulations to investigate how protonation of conserved Asp-Tyr dyads (Asp256-Tyr646 and Asp645-Tyr257) in\n                    <jats:italic>Mycobacterium smegmatis<\/jats:italic>\n                    (\n                    <jats:italic>Msmg<\/jats:italic>\n                    ) MmpL3 regulates conformational changes and TMM binding. Protonation at Asp256 induces an open dyad conformation, increases local water accessibility, and is associated with a tendency toward more open configurations of the periplasmic binding pocket. In contrast, protonation at Asp645 stabilizes a closed dyad conformation, reduces water accessibility, and narrows the transmembrane binding pocket. These findings support a proposed sequential protonation model in which protonation-dependent conformational changes are allosterically coupled to substrate translocation.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1014880","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T17:54:31Z","timestamp":1792605271000},"page":"e1014880","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proton transport drives allosteric conformational changes in the MmpL3 transporter"],"prefix":"10.1371","volume":"22","author":[{"given":"Lixinhao","family":"Yang","sequence":"first","affiliation":[{"name":"School of Chemistry and Biochemistry, Georgia Institute of Technology","place":["Atlanta, Georgia, United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. Jeffrey","family":"North","sequence":"additional","affiliation":[{"name":"Creighton University","place":["Omaha, Nebraska, United States of America"],"department":["Department of Pharmacy Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen I.","family":"Zgurskaya","sequence":"additional","affiliation":[{"name":"University of Oklahoma","place":["Norman, Oklahoma, United States of America"],"department":["Department of Chemistry and Biochemistry"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Jackson","sequence":"additional","affiliation":[{"name":"Mycobacteria Research Laboratories","place":["Fort Collins, Colorado, United States of America"],"department":["Department of Microbiology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1510-7842","authenticated-orcid":true,"given":"James C.","family":"Gumbart","sequence":"additional","affiliation":[{"name":"School of Chemistry and Biochemistry, Georgia Institute of Technology","place":["Atlanta, Georgia, United States of America"]},{"name":"School of Physics, Georgia Institute of Technology","place":["Atlanta, Georgia, United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,21]]},"reference":[{"key":"pcbi.1014880.ref001","volume-title":"Global Tuberculosis Report 2025","author":"World Health Organization","year":"2025"},{"issue":"9","key":"pcbi.1014880.ref002","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1016\/j.cmi.2023.07.013","article-title":"Recent advances in the treatment of tuberculosis","volume":"30","author":"I Motta","year":"2024","journal-title":"Clin Microbiol Infect"},{"issue":"10","key":"pcbi.1014880.ref003","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1038\/nm.4177","article-title":"Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure","volume":"22","author":"ST Malherbe","year":"2016","journal-title":"Nat Med"},{"issue":"1","key":"pcbi.1014880.ref004","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/bcp.15908","article-title":"No action is without its side effects: Adverse drug reactions and missed doses of antituberculosis therapy, a scoping review","volume":"90","author":"EG Dixon","year":"2024","journal-title":"Br J Clin Pharmacol"},{"issue":"1","key":"pcbi.1014880.ref005","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41533-020-0179-x","article-title":"Interventions to improve medication adherence in tuberculosis patients: a systematic review of randomized controlled studies","volume":"30","author":"IS Pradipta","year":"2020","journal-title":"NPJ Prim Care Respir Med"},{"issue":"3","key":"pcbi.1014880.ref006","doi-asserted-by":"crossref","first-page":"317","DOI":"10.3390\/antibiotics3030317","article-title":"Drug Resistance Mechanisms in Mycobacterium tuberculosis","volume":"3","author":"JC Palomino","year":"2014","journal-title":"Antibiotics (Basel)"},{"issue":"3","key":"pcbi.1014880.ref007","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.02530-18","article-title":"High prevalence of bedaquiline resistance in treatment-naive tuberculosis patients and verapamil effectiveness","volume":"63","author":"H Ghajavand","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"pcbi.1014880.ref008","first-page":"100295","article-title":"Impacts of MDR\/XDR-TB on the global tuberculosis epidemic: Challenges and opportunities","volume":"7","author":"KL Chin","year":"2024","journal-title":"Curr Res Microb Sci"},{"issue":"1","key":"pcbi.1014880.ref009","doi-asserted-by":"crossref","first-page":"19431","DOI":"10.1038\/s41598-021-98862-4","article-title":"Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid","volume":"11","author":"PJ G\u00f3mez-Gonz\u00e1lez","year":"2021","journal-title":"Sci Rep"},{"issue":"1","key":"pcbi.1014880.ref010","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1146\/annurev.bi.64.070195.000333","article-title":"The Envelope of Mycobacteria","volume":"64","author":"PJ Brennan","year":"1995","journal-title":"Annu Rev Biochem"},{"key":"pcbi.1014880.ref011","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S1472-9792(02)00089-6","article-title":"Structure, function, and biogenesis of the cell wall of Mycobacterium tuberculosis","volume":"83","author":"PJ Brennan","year":"2003","journal-title":"Tuberculosis (Edinb)"},{"key":"pcbi.1014880.ref012","doi-asserted-by":"crossref","first-page":"145","DOI":"10.5772\/59585","article-title":"Pathophysiological implications of cell envelope structure in Mycobacterium tuberculosis and related taxa.","volume-title":"Tuberculosis - 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