{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T19:43:41Z","timestamp":1791834221725,"version":"4.3.4"},"reference-count":54,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T00:00:00Z","timestamp":1767139200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T00:00:00Z","timestamp":1767139200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["757111"],"award-info":[{"award-number":["757111"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chemistry A European J"],"published-print":{"date-parts":[[2026,2,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Phosphoester bonds are fundamental components of both small molecules and polymeric biomolecules, most notably nucleic acids. Their formation from alcohol groups and phosphate is a significant challenge for living systems, as it involves substantial free\u2010energy barriers. These barriers, while hindering bond formation, also ensure the kinetic stability of the resulting biomolecular structures. This duality presents a major obstacle in understanding the emergence of RNA\u2010based systems at the origins of life, where protein enzymes capable of catalyzing such reactions were absent. Understanding the mechanisms underlying phosphoester formation is therefore essential for developing non\u2010biological catalytic strategies. In a recent proof\u2010of\u2010concept study (Benayad et\u00a0al.\n                    <jats:italic>Proc. Natl. Acad. Sci. USA<\/jats:italic>\n                    <jats:bold>121<\/jats:bold>\n                    e2322040121 (2024)), we demonstrated that machine\u2010learned interatomic potentials (MLIPs) can be effectively trained and employed to sample the reactive pathways of the uncatalyzed reaction in water on microsecond timescales. In this work, we significantly expand upon our previous analysis to offer a detailed molecular characterization of two families of mechanisms, associative and dissociative, each associated with a variety in the order of proton exchange events. We focus on the two protonation states of phosphate prevalent under near\u2010neutral conditions ( and ). We find that dissociative pathways are consistently lower in free\u2010energy as compared to associative ones, and that  is much more reactive than . Special attention is given to the role of the solvent, elucidating its involvement in the reaction process, as well as the contributions of proton transfer events and oxygen substitution at the phosphorus center. We conclude by proposing molecular\u2010level explanations for the observed differences in reactivity between the two phosphate protonation states based on charge redistribution during the\u00a0reaction.\n                  <\/jats:p>","DOI":"10.1002\/chem.202502428","type":"journal-article","created":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T04:03:55Z","timestamp":1767240235000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Deciphering the Molecular Mechanisms of Phosphoester Bond Formation in Abiotic Conditions With Reactive Neural Network Potentials"],"prefix":"10.1002","volume":"32","author":[{"given":"Zakarya","family":"Benayad","sequence":"first","affiliation":[{"name":"CPCV, D\u00e9partement de Chimie, \u00c9cole Normale Sup\u00e9rieure, PSL University, Sorbonne University CNRS Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"David","sequence":"additional","affiliation":[{"name":"CPCV, D\u00e9partement de Chimie, \u00c9cole Normale Sup\u00e9rieure, PSL University, Sorbonne University CNRS Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5631-5699","authenticated-orcid":false,"given":"Guillaume","family":"Stirnemann","sequence":"additional","affiliation":[{"name":"CPCV, D\u00e9partement de Chimie, \u00c9cole Normale Sup\u00e9rieure, PSL University, Sorbonne University CNRS Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,31]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0033583512000157"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2434996"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060409-092741"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0631607100"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510879103"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/10409230490460765"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a003608"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/1759-2208-3-2"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1039\/jr9580003574"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00454a018"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja01614a018"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphc.200800356"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi702106m"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja5082712"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphc.200800753"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja0200948"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-5521(99)89003-6"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/jp972182y"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja0279794"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct100547a"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.2c04259"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2322040121"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cossms.2025.101214"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physchem-062123-024417"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c03445"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50418-6"},{"key":"e_1_2_7_28_1","doi-asserted-by":"crossref","unstructured":"O.AntonandG.Stirnemann \u201cComputational Studies of Prebiotic Chemistry at the Age of Machine Learning: From Recent Breakthroughs to Future Revolutions \u201dChemRxiv(2025) href=\"https:\/\/doi.org\/10.26434\/chemrxiv\u20102025\u20104qvdz.","DOI":"10.26434\/chemrxiv-2025-4qvdz"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/jp504920s"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b06277"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c07099"},{"key":"e_1_2_7_32_1","unstructured":"J. L. A.Gardner D. F. T.du Toit C. B.Mahmoudet\u00a0al. \u201cDistillation of Atomistic Foundation Models Across Architectures and Chemical domains \u201d arXiv (2025) 2506.10956."},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpc.2018.03.016"},{"key":"e_1_2_7_34_1","first-page":"4436","article-title":"End\u2010to\u2010end Symmetry Preserving Inter\u2010Atomic Potential Energy Model for Finite and Extended Systems","volume":"31","author":"Zhang L.","year":"2018","journal-title":"Advances in Neural Information Processing Systems"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1039\/D4DD00209A"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevB.58.7260"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/jz500755u"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.3382344"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevA.38.3098"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevB.37.785"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpc.2020.107206"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/wcms.1159"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpc.2021.108171"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpc.2013.09.018"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0506-8"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/0263-7855(96)00018-5"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21787"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.25080\/Majora\u2010629e541a\u201000e"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevLett.100.020603"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpclett.0c00497"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.8b00626"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.475562"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1039\/a801266k"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1534924100"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.4965882"}],"container-title":["Chemistry \u2013 A European Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/chem.202502428","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/chem.202502428","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/chem.202502428","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T20:34:48Z","timestamp":1773002088000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/chem.202502428"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,31]]},"references-count":54,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,2,23]]}},"alternative-id":["10.1002\/chem.202502428"],"URL":"https:\/\/doi.org\/10.1002\/chem.202502428","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.26434\/chemrxiv-2023-8c1mt","asserted-by":"object"},{"id-type":"doi","id":"10.26434\/chemrxiv-2025-kbbj5","asserted-by":"object"}]},"ISSN":["0947-6539","1521-3765"],"issn-type":[{"value":"0947-6539","type":"print"},{"value":"1521-3765","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,31]]},"assertion":[{"value":"2025-07-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-31","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02428"}}