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Postgraduate Research Award"},{"name":"University of Canterbury Aho Hinatore | Accelerator PhD Scholarship","id":[{"id":"https:\/\/ror.org\/03y7q9t39","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Biomolecular Interactions Centre (UC)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Tripartite ATP-independent periplasmic (TRAP) transporters are substrate-binding protein dependent secondary transporters that leverage ion gradients to facilitate substrate translocation across bacterial and archaeal membranes. Although the structure of HiSiaQM\u2500a membrane-embedded TRAP subunit from the human pathogen Haemophilus influenzae \u2500has recently been determined, its transport mechanism is not fully understood. Given the likely importance of lipid interactions and ion coordination dynamics to the transport cycle, we applied multiscale molecular dynamics simulations to investigate these two complementary aspects of HiSiaQM function. Our simulations validated an experimentally identified lipid-binding site (BS1) and provided insight into its lipid-binding dynamics. BS1 is preferentially occupied by the anionic POPG, which is stabilized through persistent hydrogen bonds involving residues H100, R104, and R181. Additionally, our simulations revealed a novel, less stable lipid-binding site (BS2) that is selectively occupied by POPE. We suggest distinct lipid-binding behaviors for POPG and POPE, with POPG forming more persistent interactions at BS1 and POPE engaging more transiently at BS2; however, these remain to be tested experimentally. Analysis of sodium ion coordination at two known binding sites (Na1 and Na2) revealed contrasting dynamics: Na1 exhibited stable ion retention through backbone carbonyl coordination, while Na2 displayed lower stability due to involvement of the flexible side chain of T561. Geometric tunnel analysis identified possible sodium-exit pathways, supporting a working hypothesis that Na1 may act as a stable anchoring site and Na2 may function as a transient ion-exchange point during the transport cycle. Collectively, our findings provide mechanistic insights into how specific lipid interactions and sodium ion coordination could modulate HiSiaQM transporter function.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c01356","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T20:02:06Z","timestamp":1788897726000},"page":"11991-12008","source":"Crossref","is-referenced-by-count":0,"title":["Distinct Lipid\nBinding Dynamics and Sodium Ion Coordination\nin the TRAP Transporter\n                    <i>Hi<\/i>\n                    SiaQM Revealed by Multiscale\nMolecular Dynamics Simulations"],"prefix":"10.1021","volume":"66","author":[{"given":"Senwei","family":"Quan","sequence":"first","affiliation":[{"name":"University of Auckland , , ,","place":["Auckland, New Zealand, 1010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James S.","family":"Davies","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute , , ,","place":["Sydney, NSW, Australia, 2010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel A.","family":"North","sequence":"additional","affiliation":[{"name":"University of Sydney , , , ,","place":["Sydney, NSW, Australia, 2010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5611-3010","authenticated-orcid":true,"given":"Kelsi R.","family":"Hall","sequence":"additional","affiliation":[{"name":"University of Canterbury , , ,","place":["Christchurch, New Zealand, 8140"]},{"name":"University of Auckland , , ,","place":["Auckland, New Zealand, 1010"]},{"name":"University of Canterbury , , ,","place":["Christchurch, New Zealand, 8140"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam S.","family":"Turk","sequence":"additional","affiliation":[{"name":"University of Canterbury , , ,","place":["Christchurch, New Zealand, 8140"]},{"name":"University of Canterbury , , ,","place":["Christchurch, New Zealand, 8140"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Newton-Vesty","sequence":"additional","affiliation":[{"name":"University of Canterbury , , ,","place":["Christchurch, New Zealand, 8140"]},{"name":"University of Canterbury , , ,","place":["Christchurch, New Zealand, 8140"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renwick C. J.","family":"Dobson","sequence":"additional","affiliation":[{"name":"University of Canterbury , , ,","place":["Christchurch, New Zealand, 8140"]},{"name":"University of Auckland , , ,","place":["Auckland, New Zealand, 1010"]},{"name":"University of Canterbury , , ,","place":["Christchurch, New Zealand, 8140"]},{"name":"University of Melbourne , , Parkville, , ,","place":["Melbourne, Victoria, Australia, 3010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5699-1726","authenticated-orcid":true,"given":"Jane R.","family":"Allison","sequence":"additional","affiliation":[{"name":"University of Auckland , , ,","place":["Auckland, New Zealand, 1010"]},{"name":"University of Canterbury , , ,","place":["Christchurch, New Zealand, 8140"]},{"name":"University of Auckland , , ,","place":["Auckland, New Zealand, 1010"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"2026092810072405700_cit1","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/978-3-030-18768-2_9","article-title":"Secondary Active\nTransporters","volume-title":"Bacterial Cell Walls and\nMembranes","author":"Bosshart","year":"2019"},{"key":"2026092810072405700_cit2","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1159\/000099643","article-title":"Tripartite ATP-Independent Periplasmic\nTransporters: Application of a Relational Database for Genome-Wide\nAnalysis of Transporter Gene Frequency and Organization","author":"Mulligan","year":"2007","journal-title":"J. Mol. Microbiol. Biotechnol."},{"issue":"17","key":"2026092810072405700_cit3","doi-asserted-by":"publisher","first-page":"5482","DOI":"10.1128\/jb.179.17.5482-5493.1997","article-title":"TRAP Transporters:\nA New Family of Periplasmic Solute Transport Systems Encoded by the\ndctPQM Genes of Rhodobacter Capsulatus and by Homologs in Diverse\nGram-Negative Bacteria","volume":"179","author":"Forward","year":"1997","journal-title":"J. Bacteriol."},{"issue":"9","key":"2026092810072405700_cit4","doi-asserted-by":"publisher","first-page":"5291","DOI":"10.1128\/IAI.73.9.5291-5300.2005","article-title":"Novel Sialic\nAcid Transporter of Haemophilus Influenzae","volume":"73","author":"Allen","year":"2005","journal-title":"Infect. 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