{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:35:05Z","timestamp":1790879705726,"version":"4.1.0"},"reference-count":64,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Food Science &amp;amp; Nutrition"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    This study aims to isolate and identify endogenous peptides with angiotensin\u2010converting enzyme (ACE) inhibitory activity from red millet Huangjiu and to systematically elucidate their molecular mechanisms of action. Utilizing ultrafiltration, gel chromatography, and reversed\u2010phase high\u2010performance liquid chromatography (RP\u2010HPLC) followed by electrospray ionization tandem mass spectrometry (ESI\u2010MS\/MS) analysis, the tyrosine\u2010arginine dipeptide (Tyr\u2010Arg) was successfully identified. In\u00a0vitro assays demonstrated that Tyr\u2010Arg possesses moderate ACE inhibitory activity, with a half\u2010maximal inhibitory concentration (IC\n                    <jats:sub>50<\/jats:sub>\n                    ) value of 158.93\u2009\u00b1\u20090.39\u2009\u03bcM. Moreover, molecular docking analysis revealed that Tyr\u2010Arg binds to ACE via hydrogen bonding, \u03c0\u2010alkyl interactions, and van der Waals forces. Notably, the binding site was located outside the catalytic core, suggesting that Tyr\u2010Arg functions as a non\u2010competitive or allosteric inhibitor by inducing conformational changes in the enzyme. This mechanism was further corroborated by molecular dynamics (MD) simulations, which showed that the binding triggers a transition to a more open enzyme state, thereby obstructing substrate recognition or product release. MD simulations, integrated with molecular mechanics\/generalized born surface area (MM\/GBSA) calculations, substantiated that the Tyr\u2010Arg\/ACE complex underwent significant structural expansion, as evidenced by the increased radius of gyration (\n                    <jats:italic>Rg<\/jats:italic>\n                    ) and solvent\u2010accessible surface area (SASA), which stabilized after 80\u2009ns in the late stage of the simulation. Despite the extensive expansion and the consequent high root mean square deviation (RMSD), the complex achieved a stable binding conformation during the final 20\u2009ns, yielding a total binding free energy of \u22127.88\u2009kcal\/mol. The binding mechanism is primarily driven by a synergy of non\u2010polar interactions and electrostatic attraction; however, the electrostatic component is notably offset by the energetic costs associated with polar desolvation. Additionally, free energy landscape (FEL) analysis revealed the step\u2010wise sequential conformational transition pathway, identifying the global energy minima that stabilize the complex and prevent ligand dissociation, even in the face of substantial structural rearrangements observed during the 100\u2009ns simulation. This study elucidates the molecular basis of ACE inhibition by Tyr\u2010Arg, providing a scientific foundation and novel insights for the valorization of functional components in traditional fermented foods.\n                  <\/jats:p>","DOI":"10.1002\/fsn3.71749","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T02:05:16Z","timestamp":1776823516000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Isolation, Purification, Identification, and In\u00a0Vitro\n                    <scp>ACE<\/scp>\n                    Inhibitory Activity of Tyrosine\u2010Arginine Dipeptide From Red Millet Huangjiu"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0162-8077","authenticated-orcid":false,"given":"Jie","family":"Li","sequence":"first","affiliation":[{"name":"Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology  Nanyang 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