{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:53:50Z","timestamp":1792068830802,"version":"4.4.0"},"reference-count":60,"publisher":"American Chemical Society (ACS)","issue":"41","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The acid-catalyzed hydrolysis mechanism of the N-glycosidic bond in pyrimidine 2\u2032,3\u2032-didehydro-2\u2032,3\u2032-dideoxynucleosides (d4Ns), including d4U, d4T, d4C, and d4FC, was investigated using molecular dynamics (MD) simulations to refine microsolvated models, followed by density functional theory (DFT) calculations at the M06-2X(CPCM)\/6-31+G(d) level of theory, with single-point energies refined at the M06-2X(CPCM)\/6-311++G(d,p) level. Three plausible pathways\u2500\u03b1-path (inversion at C1\u2032), \u03b2-path (retention at C1\u2032), and \u03b3-path (aromatization to form a furfuryl alcohol)\u2500were evaluated. The first stage, cleavage of the N-glycosidic bond to form an oxacarbenium ion intermediate, is the rate-determining step (RDS) for all pathways. Acidic conditions dramatically catalyze the hydrolysis, lowering the activation free energy by approximately 10 kcal mol\u20131 compared to neutral conditions. The \u03b3-path exhibits a distinct kinetic and thermodynamic advantage for d4U and d4T, driven by aromatization of the furfuryl alcohol sugar, which aligns with experimental observations of \u03b3-product formation. The 5-methyl group in d4T increases the activation barrier relative to d4U, while the 5-fluoro group in d4FC lowers the barrier by \u223c2 kcal mol\u20131 compared to d4C, indicating an electron-withdrawing promoting effect. Heterolytic dissociation of the N-glycosidic bond is favored over homolytic dissociation in both gas and aqueous phases, consistent with the charge-separated intermediates identified. Nucleus-independent chemical shift (NICS) analyses quantify the increasing aromaticity along the \u03b3-path, rationalizing its thermodynamic favorability. These computational insights elucidate how nucleobase protonation and substituent effects govern the stability of the glycosidic bond and the unusual formation of \u03b3-cleavage products in acidic d4N hydrolysis.<\/jats:p>","DOI":"10.1021\/acs.jpcb.6c03919","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:01:36Z","timestamp":1791313296000},"page":"10836-10847","source":"Crossref","is-referenced-by-count":0,"title":["Aromatization-Driven\nHydrolysis of Pyrimidine d4Ns\nunder Acidic Conditions: The Preferential \u03b3-Pathway to\nFurfuryl Alcohols"],"prefix":"10.1021","volume":"130","author":[{"given":"Yang","family":"Jiang","sequence":"first","affiliation":[{"name":"Neijiang Normal University , , ,","place":["Neijiang, China, 641100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yang","sequence":"additional","affiliation":[{"name":"Xihua University , , ,","place":["Chengdu, China, 610039"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongquan","family":"Shi","sequence":"additional","affiliation":[{"name":"Xihua University , , ,","place":["Chengdu, China, 610039"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3354-2327","authenticated-orcid":true,"given":"Yi","family":"Zeng","sequence":"additional","affiliation":[{"name":"Xihua University , , ,","place":["Chengdu, China, 610039"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"2026101508061255000_cit1","doi-asserted-by":"publisher","first-page":"1897","DOI":"10.1042\/BCJ20253400","article-title":"The Energy Landscape\nof N-Ribosidic Bond Cleavage Catalysed by 2\u2019-Deoxynucleoside\n5\u2019-Phosphate N-Hydrolase 1","volume":"482","author":"Carberry","year":"2025","journal-title":"Biochem. 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