{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T05:24:25Z","timestamp":1786944265518,"version":"build-2736575974"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>Baicalein was examined in a selected docking-derived peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3) ligand-binding-domain (LBD) model to test whether pocket association, local helix 12 (H12) organization, and canonical activation function-2 (AF-2) anchoring were coupled under the sampled simulation conditions. Because no baicalein-bound PPAR\u03b3 cocrystal structure was used, the results are interpreted as a selected-pose molecular dynamics model rather than as a definitive experimental binding mode. Three independent 100-ns replicas were analyzed with bound-state filtering, H12 and AF-2 descriptors, arm-resolved energetic decomposition, interaction fingerprints, a local Tyr473-engagement potential of mean force (PMF), and exploratory state annotation. Baicalein remained spatially associated with the ligand-binding pocket by the minimum-distance and center-of-mass criteria, whereas pocket-shell contact persistence was replica-dependent, with retained fractions of 94.20%, 94.00%, and 71.64% in replicas 1\u20133. Within bound-state-filtered frames and under the selected neutral baicalein\/HIE histidine model, direct ligand hydrogen bonds to Ser289, His323, His449, and Tyr473 were not detected, and the AF-2 anchor-panel union occupancy was 0.00%. This anchor-negative pattern occurred despite measurable local H12 order, indicating that local H12 structural persistence and canonical AF-2 anchor assembly were separable in the selected model. Arm-resolved molecular mechanics\/generalized Born surface area (MM\/GBSA) descriptors and ProLIF fingerprints supported mixed Arm II\/Arm III participation, with recurrent van der Waals contacts involving Cys285, Ile341, Leu330, Leu333, Arg288, and Ile326. The local Tyr473 PMF favored a displaced baicalein geometry, with a minimum at 0.66 nm along the Tyr473 hydroxyl-to-ligand-acceptor coordinate. Limited ligand-protonation and His323\/His449-tautomer sensitivity screens did not recover persistent canonical AF-2 anchoring under the tested short-screen conditions. Exploratory state analysis resolved in-pocket heterogeneity but did not identify a descriptor-supported state with persistent canonical AF-2 anchoring. These simulations support a constrained structural model in which baicalein samples a pocket-associated, measurably H12-organized, anchor-negative PPAR\u03b3 ensemble stabilized by non-canonical pocket interactions. The interpretation is limited to simulation descriptors and does not establish receptor activation, partial agonism, phosphorylation regulation, or transcriptional output.<\/jats:p>","DOI":"10.3389\/fmolb.2026.1870075","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T04:32:00Z","timestamp":1786941120000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular dynamics analysis of a docking-derived baicalein\u2013PPAR\u03b3 ligand-binding-domain model suggests a pocket-associated AF-2-anchor-silent ensemble"],"prefix":"10.3389","volume":"13","author":[{"given":"Xingyuan","family":"Kou","sequence":"first","affiliation":[{"name":"Department of Radiology, Jianyang People\u2019s Hospital","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Changde Hospital, Xiangya School of Medicine, Central South University, The First People\u2019s Hospital of Changde City","place":["Changde, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Traditional Chinese Medicine, Changsha Medical University","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Youjiang Medical University for Nationalities","place":["Baise, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/nm.3159","article-title":"PPAR\u03b3 signaling and metabolism: the good, the bad and the future","volume":"19","author":"Ahmadian","year":"2013","journal-title":"Nat. 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