{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:15:55Z","timestamp":1785161755979,"version":"3.55.0"},"reference-count":43,"publisher":"American Chemical Society (ACS)","issue":"14","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["T2350008"],"award-info":[{"award-number":["T2350008"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"International Partnership Program of the Chinese Academy of Sciences","award":["029GJHZ2024057GC"],"award-info":[{"award-number":["029GJHZ2024057GC"]}]},{"name":"Jilin Province Science and Technology Program","award":["20260101011JJ"],"award-info":[{"award-number":["20260101011JJ"]}]},{"name":"Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project","award":["2021ZD0203000(2021ZD0203003)"],"award-info":[{"award-number":["2021ZD0203000(2021ZD0203003)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Methamphetamine (METH) exerts its stimulant and addictive effects primarily through interactions with the human dopamine transporter (hDAT), yet the molecular origins of the pronounced stereoselectivity between its S- and R-enantiomers remain poorly understood. Here, we employed all-atom molecular dynamics simulations combined with free-energy calculations and kinetic analyses to elucidate the atomic-level mechanisms underlying the stereoselective recognition of METH by hDAT. Our results reveal that S-METH binds more strongly and forms more stable interaction networks with outward-facing and occluded conformations of hDAT than R-METH. Kinetic analyses further show that S-METH associates with the outward-facing transporter more rapidly than R-METH. Importantly, S-METH promotes a thermodynamically favorable and kinetically accelerated transition from the outward-facing to the occluded state while simultaneously increasing the free-energy barrier and slowing the transition toward the inward-facing state. This dual effect effectively traps hDAT in a long-lived occluded state. In contrast, R-METH exhibits weaker binding interactions and less pronounced modulation of transporter conformational dynamics. Together, these findings provide a comprehensive thermodynamic and kinetic framework for understanding the chiral selectivity of hDAT toward METH enantiomers and offer mechanistic insight into the markedly different pharmacological potencies of S- and R-METH. The mechanistic principles revealed here may inform the rational design of dopamine transporter modulators with optimized binding thermodynamics and conformational kinetic profiles.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c01830","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T02:14:06Z","timestamp":1783563246000},"page":"8533-8544","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Mechanism\nof Chiral Recognition of R- and\nS-Methamphetamine by the Human Dopamine Transporter: Insights\nfrom Thermodynamic and Kinetic Analyses"],"prefix":"10.1021","volume":"66","author":[{"given":"Cong","family":"Zhang","sequence":"first","affiliation":[{"name":"Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , , , ,","place":["Changchun, Jilin, China, 130022"]},{"name":"University of Science and Technology of China , , , ,","place":["Hefei, Anhui, China, 230026"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , , , ,","place":["Changchun, Jilin, China, 130022"]},{"name":"University of Science and Technology of China , , , ,","place":["Hefei, Anhui, China, 230026"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penghui","family":"Li","sequence":"additional","affiliation":[{"name":"Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , , , ,","place":["Changchun, Jilin, China, 130022"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibo","family":"Wang","sequence":"additional","affiliation":[{"name":"Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , , , ,","place":["Changchun, Jilin, China, 130022"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3415-5612","authenticated-orcid":true,"given":"Xiaohui","family":"Wang","sequence":"additional","affiliation":[{"name":"Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , , , ,","place":["Changchun, Jilin, China, 130022"]},{"name":"University of Science and Technology of China , , , ,","place":["Hefei, Anhui, China, 230026"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"issue":"12","key":"2026072709094465400_cit1","doi-asserted-by":"publisher","DOI":"10.1056\/EVIDra2300160","article-title":"Methamphetamine Toxicities and Clinical Management","volume":"2","author":"Coffin","year":"2023","journal-title":"NEJM Evid."},{"key":"2026072709094465400_cit2","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1016\/j.pneurobio.2005.04.003","article-title":"Mechanisms of neurotransmitter\nrelease by amphetamines: a review","volume":"75","author":"Sulzer","year":"2005","journal-title":"Prog. 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Med."},{"key":"2026072709094465400_cit5","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1038\/nature14431","article-title":"Neurotransmitter\nand psychostimulant\nrecognition by the dopamine transporter","volume":"521","author":"Wang","year":"2015","journal-title":"Nature"},{"key":"2026072709094465400_cit6","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.neuroscience.2013.11.059","article-title":"N-terminus regulation\nof VMAT2 mediates methamphetamine-stimulated\nefflux","volume":"259","author":"Torres","year":"2014","journal-title":"Neuroscience"},{"issue":"1","key":"2026072709094465400_cit7","doi-asserted-by":"publisher","first-page":"10652","DOI":"10.1038\/ncomms10652","article-title":"Mechanisms\nof amphetamine action illuminated through\noptical monitoring of dopamine synaptic vesicles in Drosophila brain","volume":"7","author":"Freyberg","year":"2016","journal-title":"Nat. Commun."},{"key":"2026072709094465400_cit8","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1038\/npp.2017.291","article-title":"Methamphetamine\nInduces Dopamine Release in the Nucleus Accumbens Through a Sigma\nReceptor-Mediated Pathway","volume":"43","author":"Hedges","year":"2018","journal-title":"Neuropsychopharmacology"},{"issue":"1","key":"2026072709094465400_cit9","doi-asserted-by":"publisher","first-page":"2228","DOI":"10.1038\/s41467-017-02087-x","article-title":"The sigma-1 receptor\nmodulates methamphetamine dysregulation of dopamine neurotransmission","volume":"8","author":"Sambo","year":"2017","journal-title":"Nat. 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Theory Comput."},{"issue":"6","key":"2026072709094465400_cit31","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1016\/j.neuron.2018.02.016","article-title":"Differential control\nof axonal and somatic resting\npotential by voltage-dependent conductances in cortical Layer 5 pyramidal\nneurons","volume":"97","author":"Hu","year":"2018","journal-title":"Neuron"},{"key":"2026072709094465400_cit32","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual\nmolecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. 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A."},{"key":"2026072709094465400_cit40","doi-asserted-by":"publisher","first-page":"1420","DOI":"10.1021\/ct500040r","article-title":"Assessing\nthe Reliability of the\nDynamics Reconstructed from Metadynamics","volume":"10","author":"Salvalaglio","year":"2014","journal-title":"J.\nChem. Theory Comput."},{"key":"2026072709094465400_cit41","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1523\/JNEUROSCI.2796-07.2008","article-title":"Currents in response\nto rapid concentration jumps of amphetamine uncover novel aspects\nof human dopamine transporter function","volume":"28","author":"Erreger","year":"2008","journal-title":"J. Neurosci."},{"issue":"6","key":"2026072709094465400_cit42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2114204120","article-title":"Persistent binding at\ndopamine transporters determines sustained psychostimulant effects","volume":"120","author":"Niello","year":"2023","journal-title":"Proc. Natl. Acad. Sci. U. S. 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