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HuR contains tandem RNA recognition motifs (RRM1 and RRM2) that undergo substantial rearrangements between an apo open state and an RNA\u2010bound closed conformation. Here, we investigated both states using molecular dynamics (MD) simulations. While the RNA\u2010bound complex maintained a stable closed architecture, the apo form displayed extensive interdomain motions, highlighting the intrinsic flexibility of HuR. Because conventional MD simulations failed to capture the open\u2010to\u2010closed transition, we developed a novel application of Supervised MD (SuMD), previously employed for intermolecular recognition processes, to characterize HuR intramolecular domain closure. Using a multistep supervision protocol based on selected interdomain residue pairs, SuMD reproduced a closed conformation resembling the experimental RNA\u2010bound structure and identified a plausible reclosure pathway. Per\u2013residue interaction analyses revealed key contributions from the RRM1\u2013RRM2 linker region, particularly Arg97, together with Arg136 and Arg147 of RRM2, consistent with mutagenesis data. These findings extend the applicability of SuMD to intramolecular conformational transitions, provide mechanistic insight into HuR domain closure, and offer a structural framework for identifying druggable conformational states for future HuR\u2010targeted drug discovery.<\/jats:p>","DOI":"10.1002\/cmdc.70523","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T06:25:04Z","timestamp":1791181504000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Capturing Hu Antigen R Domain Closure Through Supervised Molecular Dynamics Simulations"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1605-2904","authenticated-orcid":false,"given":"Chiara","family":"Cavastracci Strascia","sequence":"first","affiliation":[{"name":"Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences University of Padova  Padova 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