{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T14:19:11Z","timestamp":1789395551761,"version":"build-2803163510"},"reference-count":88,"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\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["21773214"],"award-info":[{"award-number":["21773214"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22473100"],"award-info":[{"award-number":["22473100"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Key Project of the Joint Fund for Science and Technology Research and Development in Henan Province","doi-asserted-by":"publisher","award":["232301420008"],"award-info":[{"award-number":["232301420008"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Outstanding Youth Science Foundation Project of Henan Province","doi-asserted-by":"publisher","award":["252300421039"],"award-info":[{"award-number":["252300421039"]}],"id":[{"id":"10.13039\/na","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>The detailed mechanism of halohydrin dehalogenase (HHDH)-catalyzed ring-expansion reaction between spiro-epoxides and the nucleophile OCN\u2013 to form spiro-oxazolidinones was investigated using molecular docking, molecular dynamics (MD) simulations, and quantum mechanics\/molecular mechanics (QM\/MM) calculations. Molecular docking and molecular mechanics\/Poisson\u2013Boltzmann surface area (MM-PBSA) results revealed that the R-configurational substrate exhibited significantly superior binding affinity compared to the S-configurational one, validating the stable binding mode within the enzyme\u2032s active pocket. The fundamental pathway initiates with the nucleophilic attack of OCN\u2013 accompanied by proton transfer, which is followed by ring closure coupled with a proton transfer to form a five-membered ring. A total of four possible selective nucleophilic attack pathways were evaluated, and the most energetically favorable pathway associated with the R-configurational product has an energy barrier of 17.1 kcal\/mol, which is close to the experimental value of 18.1 kcal\/mol derived from kinetic parameters. This study provides valuable theoretical insights for the future engineering of HHDHs for chiral spiro-oxazolidinone synthesis.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c02380","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T21:14:51Z","timestamp":1788297291000},"page":"11305-11316","source":"Crossref","is-referenced-by-count":0,"title":["Mechanism and Origin\nof Stereoselectivity of Halohydrin\nDehalogenase-Catalyzed Ring-Expansion Reaction of Spiro-Epoxides"],"prefix":"10.1021","volume":"66","author":[{"given":"Yuwei","family":"Chen","sequence":"first","affiliation":[{"name":"Zhengzhou University , , , ,","place":["Zhengzhou, Henan, P. R. China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihao","family":"Sun","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy , ,","place":["Beijing, P. R. China, 102209"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2820-282X","authenticated-orcid":true,"given":"Donghui","family":"Wei","sequence":"additional","affiliation":[{"name":"Zhengzhou University , , , ,","place":["Zhengzhou, Henan, P. R. China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"issue":"46","key":"2026091409081761800_cit1","doi-asserted-by":"publisher","first-page":"8748","DOI":"10.1002\/anie.200701342","article-title":"Pyrrolidinyl-Spirooxindole\nNatural Products as Inspirations\nfor the Development of Potential Therapeutic Agents","volume":"46","author":"Galliford","year":"2007","journal-title":"Angew. Chem., Int. Ed."},{"issue":"5996","key":"2026091409081761800_cit2","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1126\/science.1193225","article-title":"Spiroindolones,\na Potent Compound Class for the Treatment of Malaria","volume":"329","author":"Rottmann","year":"2010","journal-title":"Science"},{"issue":"1","key":"2026091409081761800_cit3","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1039\/C6QO00555A","article-title":"Formal [3 + 2] Cycloaddition\nof \u03b1-Unsubstituted Isocyanoacetates\nand Methyleneindolinones: Enantioselective Synthesis of Spirooxindoles","volume":"4","author":"Peng","year":"2017","journal-title":"Org. Chem. Front."},{"issue":"4","key":"2026091409081761800_cit4","doi-asserted-by":"publisher","DOI":"10.1007\/s00894-026-06687-7","article-title":"Synthetic Advances,\nPharmacological Prospects, and Molecular Insights of Spirooxindoles:\nA Comprehensive Review","volume":"32","author":"Khdr","year":"2026","journal-title":"J. Mol. Model."},{"issue":"19","key":"2026091409081761800_cit5","doi-asserted-by":"publisher","first-page":"3988","DOI":"10.1039\/D6OB00460A","article-title":"Visible-Light-Induced\nPhotochemical Synthesis of Spirooxindoles Comprising Carbocyclic Scaffolds","volume":"24","author":"Borbhyuan","year":"2026","journal-title":"Org. Biomol. Chem."},{"issue":"5","key":"2026091409081761800_cit6","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1007\/s40262-017-0601-x","article-title":"Clinical Pharmacokinetics\nand Pharmacodynamics\nof Oxazolidinones","volume":"57","author":"Roger","year":"2018","journal-title":"Clin. Pharmacokinet."},{"issue":"9","key":"2026091409081761800_cit7","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1080\/17460441.2016.1195367","article-title":"The Utilization of Spirocyclic Scaffolds in Novel Drug\nDiscovery","volume":"11","author":"Zheng","year":"2016","journal-title":"Expert Opin. Drug Discovery"},{"issue":"6","key":"2026091409081761800_cit8","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1080\/17460441.2022.2055544","article-title":"Recent in Vivo Advances\nof Spirocyclic Scaffolds for Drug Discovery","volume":"17","author":"Batista","year":"2022","journal-title":"Expert Opin. Drug Discovery"},{"issue":"15","key":"2026091409081761800_cit9","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.4155\/fmc-2022-0079","article-title":"Recent Advances in\nOxazolidinones as Antituberculosis Agents","volume":"14","author":"Lu","year":"2022","journal-title":"Future\nMed. Chem."},{"issue":"22","key":"2026091409081761800_cit10","doi-asserted-by":"publisher","DOI":"10.3390\/molecules24224165","article-title":"Spirocyclic\nMotifs in Natural Products","volume":"24","author":"Chupakhin","year":"2019","journal-title":"Molecules"},{"issue":"2\u20133","key":"2026091409081761800_cit11","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1016\/0014-2999(95)00608-7","article-title":"Fenspiride: An Anti-Inflammatory Drug with Potential\nBenefits in the Treatment of Endotoxemia","volume":"294","author":"De Castro","year":"1995","journal-title":"Eur.\nJ. Pharmacol."},{"issue":"5","key":"2026091409081761800_cit12","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1183\/09031936.97.10051015","article-title":"Pre- and Postjunctional\nInhibitory\nEffects of Fenspiride on Guinea-Pig Bronchi","volume":"10","author":"Girard","year":"1997","journal-title":"Eur. Respir. J."},{"issue":"1","key":"2026091409081761800_cit13","doi-asserted-by":"publisher","first-page":"9","DOI":"10.2174\/1874104501711010009","article-title":"Synthesis\nand Functional Evaluation\nof Novel Aldose Reductase Inhibitors Bearing a Spirobenzopyran Scaffold","volume":"11","author":"Digiacomo","year":"2017","journal-title":"Open Med. Chem. J."},{"key":"2026091409081761800_cit14","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.ejmech.2012.02.045","article-title":"Progresses in the Pursuit of Aldose\nReductase Inhibitors:\nThe Structure-Based Lead Optimization Step","volume":"51","author":"Ramunno","year":"2012","journal-title":"Eur. J. Med. Chem."},{"issue":"11","key":"2026091409081761800_cit15","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1021\/acsmedchemlett.8b00306","article-title":"Optimization\nof Preclinical Metabolism for Somatostatin Receptor Subtype 5-Selective\nAntagonists","volume":"9","author":"Liu","year":"2018","journal-title":"ACS Med. Chem. Lett."},{"issue":"19","key":"2026091409081761800_cit16","doi-asserted-by":"publisher","first-page":"10680","DOI":"10.1021\/acs.joc.7b01728","article-title":"[3 + 2] Cycloaddition of Azaoxyallyl Cations with Cyclic\nKetones: Access to Spiro-4-Oxazolidinones","volume":"82","author":"Shao","year":"2017","journal-title":"J.\nOrg. Chem."},{"issue":"16","key":"2026091409081761800_cit17","doi-asserted-by":"publisher","first-page":"4086","DOI":"10.1039\/D3QO00820G","article-title":"Synthesis of Polysubstituted Oxazolidinones via Regioselective Addition of Azonaphthalenes","volume":"10","author":"Li","year":"2023","journal-title":"Org. Chem. Front."},{"issue":"8","key":"2026091409081761800_cit18","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1002\/adsc.202300118","article-title":"Electrochemical Dearomative\nAmination of Phenol Derivatives: Access\nto Spirooxazolidinones","volume":"365","author":"Wan","year":"2023","journal-title":"Adv. Synth. Catal."},{"issue":"2","key":"2026091409081761800_cit19","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1021\/acs.chemrev.7b00203","article-title":"Role of Biocatalysis in Sustainable Chemistry","volume":"118","author":"Sheldon","year":"2018","journal-title":"Chem. Rev."},{"issue":"18","key":"2026091409081761800_cit20","doi-asserted-by":"publisher","first-page":"14204","DOI":"10.1021\/acs.jafc.6c01422","article-title":"Lipase-Catalyzed\nEnantioselective Resolution of Chiral Pesticides and Herbicides: Advances\nin Biocatalysis and Enzyme Engineering","volume":"74","author":"Hu","year":"2026","journal-title":"J. Agric.\nFood Chem."},{"issue":"11","key":"2026091409081761800_cit21","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1002\/chir.23498","article-title":"Biocatalysis:\nA Smart and Green Tool for the Preparation of Chiral Drugs","volume":"34","author":"Rossino","year":"2022","journal-title":"Chirality"},{"issue":"17","key":"2026091409081761800_cit22","doi-asserted-by":"publisher","first-page":"5058","DOI":"10.1128\/JB.183.17.5058-5066.2001","article-title":"Halohydrin Dehalogenases Are Structurally\nand Mechanistically Related to Short-Chain Dehydrogenases\/Reductases","volume":"183","author":"Van Hylckama Vlieg","year":"2001","journal-title":"J. Bacteriol."},{"issue":"19","key":"2026091409081761800_cit23","doi-asserted-by":"publisher","first-page":"4933","DOI":"10.1093\/emboj\/cdg479","article-title":"Structure and Mechanism\nof a Bacterial Haloalcohol Dehalogenase: A New Variation of the Short-chain\nDehydrogenase\/Reductase Fold without an NAD(P)H Binding Site","volume":"22","author":"De Jong","year":"2003","journal-title":"EMBO J."},{"issue":"23","key":"2026091409081761800_cit24","doi-asserted-by":"publisher","first-page":"7303","DOI":"10.1128\/aem.01985-14","article-title":"Expanding\nthe Halohydrin Dehalogenase Enzyme Family: Identification of Novel\nEnzymes by Database Mining","volume":"80","author":"Schallmey","year":"2014","journal-title":"Appl. Environ. Microbiol."},{"issue":"2","key":"2026091409081761800_cit25","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1002\/adsc.202000984","article-title":"Halohydrin Dehalogenases\nand Their Potential in Industrial Application \u2013 A Viewpoint\nof Enzyme Reaction Engineering","volume":"363","author":"Blaz\u030cevic\u0301","year":"2021","journal-title":"Adv. Synth.\nCatal."},{"issue":"11","key":"2026091409081761800_cit26","doi-asserted-by":"publisher","first-page":"6285","DOI":"10.1021\/acscatal.2c00718","article-title":"Stereodivergent\nSynthesis of Epoxides and Oxazolidinones via the Halohydrin Dehalogenase-Catalyzed\nDesymmetrization Strategy","volume":"12","author":"Xu","year":"2022","journal-title":"ACS Catal."},{"issue":"4","key":"2026091409081761800_cit27","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1002\/bit.70151","article-title":"Controlling Enantioselectivity\nof Halohydrin Dehalogenase for Asymmetric Synthesis of Chiral Epichlorohydrin","volume":"123","author":"Cai","year":"2026","journal-title":"Biotechnol. Bioeng."},{"key":"2026091409081761800_cit28","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/j.bioorg.2018.09.012","article-title":"Identification and\nCharacterization of a Highly S-Enantioselective Halohydrin Dehalogenase\nfrom Tsukamurella Sp. 1534 for Kinetic Resolution of Halohydrins","volume":"81","author":"Wan","year":"2018","journal-title":"Bioorg. Chem."},{"issue":"4\u20135","key":"2026091409081761800_cit29","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1002\/adsc.200505333","article-title":"Enantioselective\nRing Opening of\nEpoxides with Cyanide Catalysed by Halohydrin Dehalogenases: A New\nApproach to Non-Racemic \u03b2-Hydroxy Nitriles","volume":"348","author":"Elenkov","year":"2006","journal-title":"Adv. Synth. Catal."},{"issue":"14\u201315","key":"2026091409081761800_cit30","doi-asserted-by":"publisher","first-page":"2279","DOI":"10.1002\/adsc.200700146","article-title":"Enzyme-Catalyzed\nNucleophilic Ring Opening of Epoxides for the Preparation of Enantiopure\nTertiary Alcohols","volume":"349","author":"Elenkov","year":"2007","journal-title":"Adv. Synth. Catal."},{"issue":"37","key":"2026091409081761800_cit31","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202205790","article-title":"Identification and Structure Analysis of an Unusual Halohydrin Dehalogenase\nfor Highly Chemo-, Regio- and Enantioselective Bio-Nitration of Epoxides","volume":"61","author":"Wang","year":"2022","journal-title":"Angew. Chem., Int. Ed."},{"issue":"12","key":"2026091409081761800_cit32","doi-asserted-by":"publisher","first-page":"2417","DOI":"10.1021\/ol800698t","article-title":"Formation\nof Enantiopure 5-Substituted Oxazolidinones through Enzyme-Catalysed\nKinetic Resolution of Epoxides","volume":"10","author":"Elenkov","year":"2008","journal-title":"Org. Lett."},{"issue":"7","key":"2026091409081761800_cit33","doi-asserted-by":"publisher","first-page":"5257","DOI":"10.1021\/acscatal.5c00819","article-title":"Engineering\nof Conserved Sequence Motif 1 Residues in Halohydrin Dehalogenase\nHheC Simultaneously Enhances Activity, Stability, and Enantioselectivity","volume":"15","author":"Staar","year":"2025","journal-title":"ACS Catal."},{"issue":"14","key":"2026091409081761800_cit34","doi-asserted-by":"publisher","first-page":"10670","DOI":"10.1021\/acscatal.4c02122","article-title":"Biocatalytic Construction\nof Spiro-Oxazolidinones\nvia Halohydrin Dehalogenase-Catalyzed Ring Expansion of Spiro-Epoxides","volume":"14","author":"Ma","year":"2024","journal-title":"ACS Catal."},{"issue":"10","key":"2026091409081761800_cit35","doi-asserted-by":"publisher","first-page":"6877","DOI":"10.1021\/acscatal.7b01854","article-title":"HheG, a Halohydrin Dehalogenase with\nActivity on Cyclic Epoxides","volume":"7","author":"Koopmeiners","year":"2017","journal-title":"ACS Catal."},{"issue":"11","key":"2026091409081761800_cit36","doi-asserted-by":"publisher","first-page":"4530","DOI":"10.1021\/acs.jcim.4c00640","article-title":"Origin of Chemoselectivity of Halohydrin\nDehalogenase-Catalyzed Epoxide Ring-Opening Reactions","volume":"64","author":"Wang","year":"2024","journal-title":"J. Chem. Inf. Model."},{"issue":"17","key":"2026091409081761800_cit37","doi-asserted-by":"publisher","first-page":"4973","DOI":"10.1021\/bi800001r","article-title":"Cyanolysis and Azidolysis\nof Epoxides by Haloalcohol Dehalogenase:\nTheoretical Study of the Reaction Mechanism and Origins of Regioselectivity","volume":"47","author":"Hopmann","year":"2008","journal-title":"Biochemistry"},{"issue":"7","key":"2026091409081761800_cit38","doi-asserted-by":"publisher","first-page":"4623","DOI":"10.1021\/acscatal.7b00901","article-title":"Catalytic Mechanisms\nfor Cofactor-Free\nOxidase-Catalyzed Reactions: Reaction Pathways of Uricase-Catalyzed\nOxidation and Hydration of Uric Acid","volume":"7","author":"Wei","year":"2017","journal-title":"ACS Catal."},{"issue":"28","key":"2026091409081761800_cit39","doi-asserted-by":"publisher","first-page":"5525","DOI":"10.1039\/D2OB00848C","article-title":"Cofactor-Free\nActVA-Orf6Monooxygenase Catalysis via Proton-Coupled\nElectron Transfer: A QM\/MM Study","volume":"20","author":"Li","year":"2022","journal-title":"Org. Biomol.\nChem."},{"issue":"1","key":"2026091409081761800_cit40","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1021\/acs.jpcb.2c03161","article-title":"Cofactor-Free\nDioxygenases-Catalyzed Reaction Pathway via Proton-Coupled Electron\nTransfer","volume":"127","author":"Zhang","year":"2023","journal-title":"J. Phys. Chem. B"},{"issue":"25","key":"2026091409081761800_cit41","doi-asserted-by":"publisher","first-page":"10436","DOI":"10.1021\/ja3006463","article-title":"Fundamental Reaction Pathway and\nFree Energy Profile for Inhibition of Proteasome by Epoxomicin","volume":"134","author":"Wei","year":"2012","journal-title":"J. Am. Chem. Soc."},{"issue":"24","key":"2026091409081761800_cit42","doi-asserted-by":"publisher","first-page":"6857","DOI":"10.1039\/C5OB00737B","article-title":"Fundamental\nReaction Pathway and\nFree Energy Profile of Proteasome Inhibition by Syringolin A (SylA)","volume":"13","author":"Wei","year":"2015","journal-title":"Org. Biomol. Chem."},{"key":"2026091409081761800_cit43","doi-asserted-by":"publisher","DOI":"10.1016\/j.compbiolchem.2020.107322","article-title":"Geo-Measures:\nA PyMOL Plugin for Protein Structure Ensembles Analysis","volume":"87","author":"Kagami","year":"2020","journal-title":"Comput. Biol. Chem."},{"issue":"2","key":"2026091409081761800_cit44","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving\nthe Speed and Accuracy of\nDocking with a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"2026091409081761800_cit45","doi-asserted-by":"publisher","first-page":"W368","DOI":"10.1093\/nar\/gki464","article-title":"H++: A Server for Estimating\npKas and Adding Missing\nHydrogens to Macromolecules","volume":"33","author":"Gordon","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"2026091409081761800_cit46","unstructured":"Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; Montgomery, J. A., Jr; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov, V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J.\n          Gaussian 16, Rev. A.03; Gaussian, Inc.: Wallingford, CT, 2016."},{"issue":"1","key":"2026091409081761800_cit47","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. Graphics"},{"issue":"9","key":"2026091409081761800_cit48","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development\nand Testing of a General Amber Force Field","volume":"25","author":"Wang","year":"2004","journal-title":"J. Comput. Chem."},{"issue":"8","key":"2026091409081761800_cit49","doi-asserted-by":"publisher","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","article-title":"ff14SB: Improving\nthe Accuracy of\nProtein Side Chain and Backbone Parameters from ff99SB","volume":"11","author":"Maier","year":"2015","journal-title":"J. Chem. Theory Comput."},{"issue":"2","key":"2026091409081761800_cit50","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison\nof Simple Potential Functions for Simulating Liquid Water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"issue":"9","key":"2026091409081761800_cit51","doi-asserted-by":"publisher","first-page":"3878","DOI":"10.1021\/ct400314y","article-title":"Routine\nMicrosecond Molecular Dynamics Simulations with AMBER on GPUs. 2.\nExplicit Solvent Particle Mesh Ewald","volume":"9","author":"Salomon-Ferrer","year":"2013","journal-title":"J. Chem.\nTheory Comput."},{"key":"2026091409081761800_cit52","unstructured":"Case, D. A.; Belfon, K.; Ben-Shalom, I. Y.; Brozell, S. R.; Cerutti, D. S.; Cheatham, T. E.; Cruzeiro, V. W. D.; Darden, T. A.; Duke, R. E.; Giambasu, G.; Gilson, M. K.; Gohlke, H.; Goetz, A. W.; Harris, R.; Izadi, S.; Kasavajhala, K.; Kovalenko, A.; Krasny, R.; Kurtzman, T.; Lee, T. S.; LeGrand, S.; Li, P.; Lin, C.; Liu, J.; Luchko, T.; Luo, R.; Man, V.; Merz, K. M.; Miao, Y.; Mikhailovskii, O.; Monard, G.; Nguyen, H.; Onufriev, A.; Pan, F.; Pantano, S.; Qi, R.; Roe, D. R.; Roitberg, A.; Sagui, C.; Schott-Verdugo, S.; Shen, J.; Simmerling, C. L.; Skrynnikov, N.; Smith, J.; Swails, J.; Walker, R. C.; Wang, J.; Wilson, L.; Wolf, R. M.; Wu, X.; York, D. M.; Kollman, P. A.\n          AMBER 2020; University of California: San Francisco, 2020."},{"issue":"9","key":"2026091409081761800_cit53","doi-asserted-by":"publisher","first-page":"3314","DOI":"10.1021\/ct300418h","article-title":"MMPBSA.Py: An Efficient Program for\nEnd-State Free Energy Calculations","volume":"8","author":"Miller","year":"2012","journal-title":"J. Chem.\nTheory Comput."},{"issue":"1\u20133","key":"2026091409081761800_cit54","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0166-1280(03)00285-9","article-title":"QUASI: A General Purpose\nImplementation of the QM\/MM Approach and Its Application to Problems\nin Catalysis","volume":"632","author":"Sherwood","year":"2003","journal-title":"J. Mol. Struct."},{"issue":"5","key":"2026091409081761800_cit55","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1002\/wcms.1183","article-title":"Machine\nLearning Methods in Chemoinformatics","volume":"4","author":"Mitchell","year":"2014","journal-title":"WIREs\nComput. Mol. Sci."},{"issue":"5","key":"2026091409081761800_cit56","doi-asserted-by":"publisher","DOI":"10.1002\/wcms.1606","article-title":"Software Update:\nThe ORCA Program System\u2500Version 5.0","volume":"12","author":"Neese","year":"2022","journal-title":"WIREs Comput. Mol. Sci."},{"issue":"1","key":"2026091409081761800_cit57","doi-asserted-by":"publisher","DOI":"10.1002\/wcms.1327","article-title":"Software Update:\nThe ORCA Program System, Version 4.0","volume":"8","author":"Neese","year":"2018","journal-title":"WIREs\nComput. Mol. Sci."},{"issue":"1","key":"2026091409081761800_cit58","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/wcms.81","article-title":"The ORCA Program\nSystem","volume":"2","author":"Neese","year":"2012","journal-title":"WIREs Comput. Mol. Sci."},{"issue":"22","key":"2026091409081761800_cit59","doi-asserted-by":"publisher","DOI":"10.1063\/5.0004608","article-title":"The ORCA Quantum\nChemistry Program Package","volume":"152","author":"Neese","year":"2020","journal-title":"J. Chem. Phys."},{"issue":"12\u201313","key":"2026091409081761800_cit60","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1080\/08927020600939830","article-title":"A Short Description\nof DL_POLY","volume":"32","author":"Smith","year":"2006","journal-title":"Mol. Simul."},{"issue":"43","key":"2026091409081761800_cit61","doi-asserted-by":"publisher","first-page":"11856","DOI":"10.1021\/jp9028968","article-title":"DL-FIND: An Open-Source\nGeometry Optimizer for Atomistic\nSimulations","volume":"113","author":"Ka\u0308stner","year":"2009","journal-title":"J. Phys. Chem. A"},{"issue":"1\u20133","key":"2026091409081761800_cit62","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1007\/BF01589116","article-title":"On the Limited Memory\nBFGS Method for Large Scale Optimization","volume":"45","author":"Liu","year":"1989","journal-title":"Math.\nProgram."},{"issue":"10","key":"2026091409081761800_cit63","doi-asserted-by":"publisher","first-page":"2177","DOI":"10.1039\/a909486e","article-title":"Linear Scaling Geometry Optimisation\nand Transition State Search in Hybrid Delocalised Internal Coordinates","volume":"2","author":"Billeter","year":"2000","journal-title":"Phys. Chem. Chem. Phys."},{"issue":"1","key":"2026091409081761800_cit64","doi-asserted-by":"publisher","DOI":"10.1063\/1.2815812","article-title":"Superlinearly Converging\nDimer Method for Transition\nState Search","volume":"128","author":"Ka\u0308stner","year":"2008","journal-title":"J. Chem. Phys."},{"issue":"15","key":"2026091409081761800_cit65","doi-asserted-by":"publisher","DOI":"10.1063\/1.5090222","article-title":"A Generally Applicable\nAtomic-Charge Dependent London Dispersion Correction","volume":"150","author":"Caldeweyher","year":"2019","journal-title":"J. Chem. Phys."},{"issue":"18","key":"2026091409081761800_cit66","doi-asserted-by":"publisher","first-page":"3297","DOI":"10.1039\/b508541a","article-title":"Balanced Basis Sets of Split Valence, Triple Zeta Valence\nand Quadruple Zeta Valence Quality for H to Rn: Design and Assessment\nof Accuracy","volume":"7","author":"Weigend","year":"2005","journal-title":"Phys. Chem. Chem. Phys."},{"issue":"7","key":"2026091409081761800_cit67","doi-asserted-by":"publisher","first-page":"5648","DOI":"10.1063\/1.464913","article-title":"Density-Functional\nThermochemistry. III. The Role of Exact Exchange","volume":"98","author":"Becke","year":"1993","journal-title":"J. Chem. Phys."},{"issue":"25","key":"2026091409081761800_cit68","doi-asserted-by":"publisher","first-page":"6703","DOI":"10.1021\/acs.jpca.5b02809","article-title":"Dispersion Corrections Improve the\nAccuracy of Both Noncovalent and Covalent Interactions Energies Predicted\nby a Density-Functional Theory Approximation","volume":"119","author":"Van Santen","year":"2015","journal-title":"J. Phys. Chem. A"},{"issue":"5","key":"2026091409081761800_cit69","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1021\/cr00005a013","article-title":"A Quantum\nTheory of Molecular Structure and Its Applications","volume":"91","author":"Bader","year":"1991","journal-title":"Chem. Rev."},{"issue":"5","key":"2026091409081761800_cit70","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1002\/jcc.22885","article-title":"Multiwfn: A Multifunctional Wavefunction Analyzer","volume":"33","author":"Lu","year":"2012","journal-title":"J. Comput. Chem."},{"issue":"15","key":"2026091409081761800_cit71","doi-asserted-by":"publisher","DOI":"10.1063\/1.3382344","article-title":"A Consistent and Accurate\nAb Initio Parametrization of Density Functional Dispersion Correction\n(DFT-D) for the 94 Elements H-Pu","volume":"132","author":"Grimme","year":"2010","journal-title":"J. Chem. Phys."},{"issue":"2","key":"2026091409081761800_cit72","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevB.37.785","article-title":"Development\nof the Colle-Salvetti\nCorrelation-Energy Formula into a Functional of the Electron Density","volume":"37","author":"Lee","year":"1988","journal-title":"Phys. Rev. B"},{"issue":"18","key":"2026091409081761800_cit73","doi-asserted-by":"publisher","first-page":"6378","DOI":"10.1021\/jp810292n","article-title":"Universal Solvation Model Based on\nSolute Electron Density and on a Continuum Model of the Solvent Defined\nby the Bulk Dielectric Constant and Atomic Surface Tensions","volume":"113","author":"Marenich","year":"2009","journal-title":"J. Phys. Chem. B"},{"issue":"2","key":"2026091409081761800_cit74","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1039\/D5QO01408E","article-title":"Origin of Chemo- and\nStereoselectivity in NHC-Catalyzed Asymmetric Intermolecular Cycloadditions\nof Hydrazone and Isatin","volume":"13","author":"Shen","year":"2026","journal-title":"Org. Chem. Front."},{"issue":"5","key":"2026091409081761800_cit75","doi-asserted-by":"publisher","first-page":"1852","DOI":"10.1039\/D5CY01566A","article-title":"Origin of Stereoselectivity in NHC-Catalyzed\nDesymmetrization of Pseudo- Para -Substituted [2.2]Paracyclophane\nDialdehydes toward Planar Chirality","volume":"16","author":"Fan","year":"2026","journal-title":"Catal.\nSci. Technol."},{"issue":"1","key":"2026091409081761800_cit76","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1021\/acscatal.5c07102","article-title":"Origin of Chemoselectivity Associated with N -Heterocyclic\nCarbenes as C1 Synthons versus Organocatalysts","volume":"16","author":"Wang","year":"2026","journal-title":"ACS Catal."},{"issue":"2","key":"2026091409081761800_cit77","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/s41929-026-01480-4","article-title":"Palladium-Catalysed Asymmetric Anti-Michael-Type\nAddition of \u03b1,\u03b2-Unsaturated Carboxylic Acids with Carboranes","volume":"9","author":"Lei","year":"2026","journal-title":"Nat. Catal."},{"key":"2026091409081761800_cit78","doi-asserted-by":"publisher","first-page":"11011","DOI":"10.1021\/acscatal.6c00306","article-title":"Ligand-Assisted\nElectron\nTransfer Drives N\u2013O Bond Cleavage Enabling Heteronuclear Copper\nOxidative Addition","volume":"16","author":"Qiao","year":"2026","journal-title":"ACS Catal."},{"issue":"22","key":"2026091409081761800_cit79","doi-asserted-by":"publisher","first-page":"19385","DOI":"10.1021\/acscatal.5c05849","article-title":"Biocatalytic\nNoncanonical Enantioconvergent Synthesis of Vicinal Diols","volume":"15","author":"Miao","year":"2025","journal-title":"ACS Catal."},{"key":"2026091409081761800_cit80","unstructured":"Legault, C. Y.; Universite\u0301 de Sherbrooke.. Cylview202020http:\/\/www.cylview.org."},{"issue":"1\u20133","key":"2026091409081761800_cit81","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1007\/s00214-007-0310-x","article-title":"The M06 Suite of\nDensity Functionals for Main Group\nThermochemistry, Thermochemical Kinetics, Noncovalent Interactions,\nExcited States, and Transition Elements: Two New Functionals and Systematic\nTesting of Four M06-Class Functionals and 12 Other Functionals","volume":"120","author":"Zhao","year":"2008","journal-title":"Theor. Chem. Acc."},{"issue":"44","key":"2026091409081761800_cit82","doi-asserted-by":"publisher","first-page":"6615","DOI":"10.1039\/b810189b","article-title":"Long-Range\nCorrected Hybrid Density Functionals with\nDamped Atom\u2013Atom Dispersion Corrections","volume":"10","author":"Chai","year":"2008","journal-title":"Phys. Chem. Chem. Phys."},{"issue":"7","key":"2026091409081761800_cit83","doi-asserted-by":"publisher","first-page":"3084","DOI":"10.1021\/ct400341p","article-title":"PTRAJ and CPPTRAJ:\nSoftware for Processing and Analysis\nof Molecular Dynamics Trajectory Data","volume":"9","author":"Roe","year":"2013","journal-title":"J. Chem.\nTheory Comput."},{"issue":"5","key":"2026091409081761800_cit84","doi-asserted-by":"publisher","first-page":"1486","DOI":"10.1039\/C2RA22886F","article-title":"Understanding the Local Reactivity\nin Polar Organic Reactions through Electrophilic and Nucleophilic\nParr Functions","volume":"3","author":"Domingo","year":"2013","journal-title":"RSC Adv."},{"issue":"20","key":"2026091409081761800_cit85","doi-asserted-by":"publisher","first-page":"6723","DOI":"10.1073\/pnas.82.20.6723","article-title":"Hardness, Softness,\nand the Fukui Function in the Electronic\nTheory of Metals and Catalysis","volume":"82","author":"Yang","year":"1985","journal-title":"Proc. Natl.\nAcad. Sci. U.S.A."},{"issue":"14","key":"2026091409081761800_cit86","doi-asserted-by":"publisher","first-page":"4049","DOI":"10.1021\/ja00326a036","article-title":"Density Functional\nApproach to the Frontier-Electron Theory of Chemical\nReactivity","volume":"106","author":"Parr","year":"1984","journal-title":"J. Am. Chem. Soc."},{"issue":"1","key":"2026091409081761800_cit87","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-58281-9","article-title":"An Analysis Method Including Orbital\nOverlap Directions for Predicting \u03c0 Electron Properties and\nReactivity Vectors","volume":"16","author":"Shi","year":"2025","journal-title":"Nat. Commun."},{"key":"2026091409081761800_cit88","unstructured":"Shi, X.; Wei, D.\n          WmView\nv2025.10.17n.d. http:\/\/www.wmview.xyz."}],"container-title":["Journal of Chemical Information\nand Modeling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jcim.6c02380","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/66\/17\/11305\/67523156\/acs.jcim.6c02380.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/66\/17\/11305\/67523156\/acs.jcim.6c02380.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:28:30Z","timestamp":1789392510000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article\/66\/17\/11305\/5340654\/Mechanism-and-Origin-of-Stereoselectivity-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,27]]},"references-count":88,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,8,27]]},"published-print":{"date-parts":[[2026,9,14]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jcim.6c02380","relation":{},"ISSN":["1549-9596","1549-960X"],"issn-type":[{"value":"1549-9596","type":"print"},{"value":"1549-960X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,27]]}}}