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Dysfunction of SERT has been linked to several neuropsychiatric disorders, including depression, anxiety and obsessive\u2010compulsive disorder. Therefore, an in\u2010depth understanding of the mechanism on an atomistic level, coupled with a quantification of transporter dynamics and the associated free energies is required. Here, we constructed Markov state models (MSMs) from extensive unbiased molecular dynamics simulations to quantify the free energy profile of serotonin (5HT) triggered SERT occlusion and explored the driving forces of the mechanism of occlusion. Our results reveal that SERT occludes via multiple intermediate conformations and show that the motion of occlusion is energetically downhill for the 5HT\u2010bound transporter. Force distribution analyses show that the interactions of 5HT with the bundle domain are crucial. During occlusion, attractive forces steadily increase and pull on the bundle domain, which leads to SERT occlusion. Some interactions become repulsive upon full occlusion, suggesting that SERT creates pressure on 5HT to promote its movement towards the cytosol.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16061-fig-0005-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.16061","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T08:21:44Z","timestamp":1707294104000},"page":"1993-2006","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Free energy profile of the substrate\u2010induced occlusion of the human serotonin transporter"],"prefix":"10.1111","volume":"168","author":[{"given":"Leticia","family":"Alves\u00a0da\u00a0Silva","sequence":"first","affiliation":[{"name":"Centre for Physiology and Pharmacology Institute of Pharmacology, Medical University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Lazzarin","sequence":"additional","affiliation":[{"name":"Centre for Physiology and Pharmacology Institute of Pharmacology, Medical University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Gradisch","sequence":"additional","affiliation":[{"name":"Centre for Physiology and Pharmacology Institute of Pharmacology, Medical University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Clarke","sequence":"additional","affiliation":[{"name":"Centre for Physiology and Pharmacology Institute of Pharmacology, Medical University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7071-8283","authenticated-orcid":false,"given":"Thomas","family":"Stockner","sequence":"additional","affiliation":[{"name":"Centre for Physiology and Pharmacology Institute of Pharmacology, Medical University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.softx.2015.06.001"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.340170408"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19\u201012\u201004705.1999"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959\u2010440X(00)00061\u20100"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.3139063"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2022.01.024"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature17629"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010019\u20101135\u20101"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct300646g"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.laa.2004.10.026"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201034630\u2010w"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00030.2009"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.101613"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.115.099036"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0217377"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1000480"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(18)32279\u20107"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/211969a0"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.1821"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0063635"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002246"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2012.07.022"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.22711"},{"key":"e_1_2_11_25_1","volume-title":"Classification and analysis of multivariate observations","author":"MacQueen J. 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