{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T14:19:15Z","timestamp":1789395555396,"version":"build-2803163510"},"reference-count":111,"publisher":"American Chemical Society (ACS)","issue":"17","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100001843","name":"Science and Engineering Research Board","doi-asserted-by":"publisher","award":["CRG\/2022\/004088"],"award-info":[{"award-number":["CRG\/2022\/004088"]}],"id":[{"id":"10.13039\/501100001843","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001843","name":"Science and Engineering Research Board","doi-asserted-by":"publisher","award":["SR\/FST\/CSII-026\/2013"],"award-info":[{"award-number":["SR\/FST\/CSII-026\/2013"]}],"id":[{"id":"10.13039\/501100001843","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000704","name":"Royal Society of Chemistry","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000704","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004541","name":"Ministry of Education, India","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004541","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>An accurate description of halogen bonding in biomolecules remains a challenge in modern biochemistry, as exemplified by the flavin-dependent human dehalogenase, iodotyrosine deiodinase. Analyses of the static crystal structure and kinetics data suggested that halogen bonding is absent in the enzyme\u2019s active site, which does not preclude its transient formation along the binding or unbinding pathway. No studies have yet explored iodotyrosine deiodinase\u2019s dynamic behavior from the perspective of halogen bonding. Here, extensive equilibrium and nonequilibrium molecular dynamics (MD) simulations together with quantum-mechanical calculations are performed to elucidate how the cooperative interplay of transient halogen bonds and stable hydrogen bonds governs substrate recognition and retention. An extra-point charge model is employed to describe \u03c3-hole of the halogen to capture its charge anisotropy in classical simulation. The isotropic steered molecular dynamics simulations and dynamic time warping algorithm identify dominant unbinding pathways for I-Tyr, Cl-Tyr, and I-Phenol. Substrate release kinetics is controlled by a stepwise disruption of key hydrogen bonds and salt bridges with K182, Y161, E157, and the flavin cofactor. Molecular dynamics simulation-derived geometries were screened, representative poses were chosen based on structural criteria, and halogen-bond-like interactions were validated through natural bond orbital and energy-decomposition analyses. Geometries consistent with halogen-bond-like interactions (0.5\u20132.0 kcal\/mol) are observed for I-Tyr and I-Phenol near the protein surface. In contrast, Cl-Tyr interactions identified solely by structural criteria largely correspond to false positives, underscoring the necessity of quantum-mechanical validation for reliably characterizing halogen-bond-like interactions. These early, short-lived halogen bonds help orient the native substrate toward a possible alternate site, triggering a communication network that grows with strong hydrogen bonds during substrate recognition. By integrating dynamic simulations with quantum-mechanical validation, this work reconciles conflicting views on halogen bonding in human iodotyrosine deiodinase, revealing transient geometries consistent with halogen-bond-like interactions alongside persistent hydrogen bonds.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c00986","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T18:28:36Z","timestamp":1788287316000},"page":"11191-11210","source":"Crossref","is-referenced-by-count":0,"title":["Halogen-Bonding-like\nInteractions Complement Hydrogen\nBonding in a Human Flavin-Dependent Dehalogenase"],"prefix":"10.1021","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4867-0970","authenticated-orcid":true,"given":"Soumyajit","family":"Karmakar","sequence":"first","affiliation":[{"name":"Indian Institute of Technology Kharagpur , , ,","place":["Kharagpur, India, 721302"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2551-1021","authenticated-orcid":true,"given":"Sabyashachi","family":"Mishra","sequence":"additional","affiliation":[{"name":"Indian Institute of Technology Kharagpur , , ,","place":["Kharagpur, India, 721302"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"2026091409072145000_cit1","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/S0076-6879(02)47014-0","article-title":"Iodothyronine\nDeiodinases","volume-title":"Methods in Enzymology","author":"Ko\u0308hrle","year":"2002"},{"key":"2026091409072145000_cit2","doi-asserted-by":"publisher","first-page":"4487","DOI":"10.1021\/acs.biochem.5b00410","article-title":"Rapid kinetics\nof dehalogenation\npromoted by iodotyrosine deiodinase from human thyroid","volume":"54","author":"Bobyk","year":"2015","journal-title":"Biochemistry"},{"key":"2026091409072145000_cit3","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1074\/jbc.M114.605964","article-title":"A switch between one-and two-electron\nchemistry of the human flavoprotein iodotyrosine deiodinase is controlled\nby substrate","volume":"290","author":"Hu","year":"2015","journal-title":"J. Biol. Chem."},{"key":"2026091409072145000_cit4","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1002\/cbic.201900619","article-title":"Halogen bonding in\nbiomimetic deiodination of thyroid hormones and their metabolites\nand dehalogenation of halogenated nucleosides","volume":"21","author":"Mondal","year":"2020","journal-title":"ChemBioChem"},{"key":"2026091409072145000_cit5","doi-asserted-by":"publisher","first-page":"4269","DOI":"10.1021\/ja210478k","article-title":"Regioselective deiodination of thyroxine by iodothyronine\ndeiodinase mimics: an unusual mechanistic pathway involving cooperative\nchalcogen and halogen bonding","volume":"134","author":"Manna","year":"2012","journal-title":"J. Am. Chem.\nSoc."},{"key":"2026091409072145000_cit6","doi-asserted-by":"publisher","DOI":"10.3390\/inorganics7030040","article-title":"Halogen bonding: A halogen-centered\nnoncovalent interaction yet to be understood","volume":"7","author":"Varadwaj","year":"2019","journal-title":"Inorganics"},{"key":"2026091409072145000_cit7","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1021\/jm3012068","article-title":"Principles\nand applications of halogen bonding in medicinal chemistry and chemical\nbiology","volume":"56","author":"Wilcken","year":"2013","journal-title":"J. Med. Chem."},{"key":"2026091409072145000_cit8","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1080\/17460441.2019.1619692","article-title":"Halogen Bonding\nin Halocarbon-protein\nComplexes and Computational Tools for Rational Drug Design","volume":"14","author":"Costa","year":"2019","journal-title":"Expert Opin. Drug Discovery"},{"key":"2026091409072145000_cit9","doi-asserted-by":"publisher","first-page":"4241","DOI":"10.1021\/acs.jctc.9b00106","article-title":"Tackling Halogenated Species with\nPBSA: Effect of Emulating the \u03c3-hole","volume":"15","author":"Nunes","year":"2019","journal-title":"J. Chem. Theory Comput."},{"key":"2026091409072145000_cit10","doi-asserted-by":"publisher","first-page":"1655","DOI":"10.1021\/acs.jmedchem.5b00997","article-title":"Computational tools to model halogen\nbonds in medicinal chemistry","volume":"59","author":"Ford","year":"2016","journal-title":"J. Med. Chem."},{"key":"2026091409072145000_cit11","doi-asserted-by":"publisher","first-page":"7464","DOI":"10.1021\/acs.jcim.3c01561","article-title":"Assessment of Halogen\nOff-Center Point-Charge Models\nUsing Explicit Solvent Simulations","volume":"63","author":"Fortuna","year":"2023","journal-title":"J. Chem.\nInf. 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Chem."},{"key":"2026091409072145000_cit19","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1021\/acs.biochem.3c00041","article-title":"Substrate electronics\ndominate the rate of reductive dehalogenation promoted by the flavin-dependent\niodotyrosine deiodinase","volume":"62","author":"Kozyryev","year":"2023","journal-title":"Biochemistry"},{"key":"2026091409072145000_cit20","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1002\/pro.3479","article-title":"Redox control of\niodotyrosine deiodinase","volume":"28","author":"Hu","year":"2019","journal-title":"Protein Sci."},{"key":"2026091409072145000_cit21","doi-asserted-by":"publisher","first-page":"3310","DOI":"10.1021\/acs.biochem.4c00639","article-title":"Flavin-Mediated Reductive\nDeiodination: Conformational\nEvents and Reactivity Pattern in the Active Site of Human Iodotyrosine\nDeiodinase","volume":"63","author":"Karmakar","year":"2024","journal-title":"Biochemistry"},{"key":"2026091409072145000_cit22","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1021\/acs.biochem.2c00037","article-title":"Sequence conservation\ndoes not always signify a functional\nimperative as observed in the nitroreductase superfamily","volume":"61","author":"Musila","year":"2022","journal-title":"Biochemistry"},{"key":"2026091409072145000_cit23","unstructured":"Day, M. A.\n          \n          Structural\nComparisons of the E. coli Prodrug-activating Nitroreductase Enzymes,\nNfsA and NfsB. Ph.D. Thesis; University\nof Birmingham2013."},{"key":"2026091409072145000_cit24","doi-asserted-by":"publisher","first-page":"3131","DOI":"10.1016\/j.jmb.2016.07.003","article-title":"Chopping\nand changing: the evolution of the flavin-dependent monooxygenases","volume":"428","author":"Mascotti","year":"2016","journal-title":"J. Mol. 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Biol. Chem."},{"key":"2026091409072145000_cit31","doi-asserted-by":"publisher","first-page":"4270","DOI":"10.1021\/acscatal.5c00619","article-title":"Zwitterionic Dual Halogen Bond-Catalyzed\nElectrophilic Bromination\nof Electron-Deficient Arenes under Mild Conditions","volume":"15","author":"Zhang","year":"2025","journal-title":"ACS Catal."},{"key":"2026091409072145000_cit32","doi-asserted-by":"publisher","DOI":"10.1002\/ange.202506525","article-title":"Taxonomy of Chemical\nBondings: Opportunities and Challenges","volume":"137","author":"Pizzi","year":"2025","journal-title":"Angew.\nChem."},{"key":"2026091409072145000_cit33","doi-asserted-by":"publisher","DOI":"10.1002\/ardp.202400740","article-title":"Halogen-based quinazolin-4\n(3H)-one\nderivatives as MCF-7 breast cancer inhibitors: Current developments\nand structure\u2013activity relationship","volume":"358","author":"Upadhyay","year":"2025","journal-title":"Arch. Pharm."},{"key":"2026091409072145000_cit34","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1021\/ar0400995","article-title":"Halogen bonding based\nrecognition processes: a world parallel to hydrogen bonding","volume":"38","author":"Metrangolo","year":"2005","journal-title":"Acc. Chem. Res."},{"key":"2026091409072145000_cit35","doi-asserted-by":"publisher","first-page":"2686","DOI":"10.1021\/ar400103r","article-title":"The halogen bond in\nthe design of functional supramolecular materials: recent advances","volume":"46","author":"Priimagi","year":"2013","journal-title":"Acc. Chem. Res."},{"key":"2026091409072145000_cit36","doi-asserted-by":"publisher","first-page":"7118","DOI":"10.1021\/cr500674c","article-title":"Halogen bonding in supramolecular chemistry","volume":"115","author":"Gilday","year":"2015","journal-title":"Chem. 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