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This pseudoknot exhibits both threaded and unthreaded long\u2010lived topologies. The influence of ligand binding on its folding is a process critical for the development of 1 PRF small\u2010molecule inhibitors. Understanding this process through unbiased molecular dynamics (MD) simulations can be facilitated by introducing collective variables (CVs) that capture the corresponding slowest dynamical modes. Here, we use spectral map (SM), a thermodynamics\u2010driven machine learning technique, to learn such CVs directly from all\u2010atom MD trajectories of the SARS\u2010CoV\u20102 RNA pseudoknot in complex with the 1 PRF inhibitor merafloxacin and its two structural analogs in neutral and ionized forms. Free\u2010energy landscapes (FELs) derived from the learned CVs indicate that ligand\u2010induced destabilization is topology\u2010selective. In the threaded pseudoknot, the inhibitors destabilize the S2 stem, while in the unthreaded pseudoknot, destabilization occurs in the S1 and S3 stems. Furthermore, the extent to which each ligand reshapes the FEL matches experimentally reported antiviral potency, whereas the protonation state qualitatively alters dynamics within the same RNA topology. Overall, our results show how pseudoknot topology, ligand type, and protonation state collectively influence the slow conformational dynamics of viral RNA and establish physiological protonation as a critical factor for modeling RNA\u2010targeted drug action.<\/jats:p>","DOI":"10.1002\/jcc.70461","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T02:41:11Z","timestamp":1783651271000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unraveling the Mechanism of Drug Binding to SARS\u2010CoV\u20102 RNA Pseudoknot With Thermodynamics\u2010Driven Machine Learning"],"prefix":"10.1002","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8204-3562","authenticated-orcid":false,"given":"Mariia","family":"Ivonina","sequence":"first","affiliation":[{"name":"Platform of Inter\/Transdisciplinary Energy Research Kyushu University  Fukuoka 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