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Mutations can alter their properties; for example, some mutations increase the stability of a functionally relevant structure at the expense of other structures\u2019 stability. Interestingly, the structural diversity a sequence produces is correlated with the number of structures it can access upon mutation. Thus, enhancing a structure\u2019s stability can lead to neutral confinement, an evolutionary dead-end in which mutational access to novel structures is increasingly difficult. If the structure is critical to biological function, how do RNA molecules escape neutral confinement? We have developed a model in which an RNA molecule\u2019s function depends on binding to a ligand, and we applied it to study sequences that fold according to RNA biophysics, also simulating their evolution. Our analyses and simulations have identified effects that decrease the selective advantage of augmenting a structure\u2019s stability. By disfavouring the evolution of highly stable structures and favouring the accumulation of genetic variation, these effects hinder neutral confinement. The most important effect stems from the sequestration of high-affinity structures in RNA-ligand complexes and their replenishment through thermal fluctuations. In this perspective, a common scenario may help to explain how RNA evolution avoids coming to a halt.<\/jats:p>","DOI":"10.1098\/rsif.2026.0102","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:21:24Z","timestamp":1782865284000},"source":"Crossref","is-referenced-by-count":0,"title":["RNA-ligand complexes and the attenuation of neutral confinement in the evolution of RNA secondary structures"],"prefix":"10.1098","volume":"23","author":[{"given":"Antonio","family":"Loreto","sequence":"first","affiliation":[{"name":"Instituto de F\u00edsica, Universidad Aut\u00f3noma de San Luis Potos\u00ed , San Luis Potosi, S.L.P., Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4450-932X","authenticated-orcid":false,"given":"Edgardo","family":"Ugalde","sequence":"additional","affiliation":[{"name":"Instituto de F\u00edsica, Universidad Aut\u00f3noma de San Luis Potos\u00ed , San Luis Potosi, S.L.P., Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9753-5807","authenticated-orcid":false,"given":"Carlos","family":"Espinosa-Soto","sequence":"additional","affiliation":[{"name":"Instituto de F\u00edsica, Universidad Aut\u00f3noma de San Luis Potos\u00ed , San Luis Potosi, S.L.P., Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"2026082409591481800_bib1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/nrg3841","article-title":"The RNA world: molecular cooperation at the origins of life","volume":"16","author":"Higgs","year":"2015","journal-title":"Nat. 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