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Here, we propose a rational ligand design strategy based on multivalency, in which ligand molecules are covalently linked into polymer-like macromolecules. Using coarse-grained molecular dynamics, we show that these \u201cpolyligands\u201d intercalate G4 multimers more efficiently than their monomeric counterparts, achieving strong stabilization through cooperative effects, even when individual ligands exhibit low intrinsic binding affinity. Polyligand intercalation induces structural changes in G4 multimers, modifying their size and stiffness. Using a quantitative polymer theory framework, we connect these structural changes with the thermal stabilization of G4 multimers. Polyligands represent a general design principle for G4-targeting molecular stabilizers, offering enhanced G4 stabilization via programmable linker length and backbone rigidity.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c01189","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T13:14:20Z","timestamp":1788354860000},"page":"11246-11258","source":"Crossref","is-referenced-by-count":0,"title":["Rational Polyligand\nDesign for G-Quadruplex\nMultimer Stabilization"],"prefix":"10.1021","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4084-6046","authenticated-orcid":true,"given":"Deniz","family":"Mostarac","sequence":"first","affiliation":[{"name":"University of Edinburgh , , ,","place":["Edinburgh, U.K., EH9 3FJ"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavio","family":"Scipione","sequence":"additional","affiliation":[{"name":"University of Rome La Sapienza , , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia","family":"Trapella","sequence":"additional","affiliation":[{"name":"University of Perugia , , ,","place":["Perugia, Italy, 06123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2314-1435","authenticated-orcid":true,"given":"Luca","family":"Bertini","sequence":"additional","affiliation":[{"name":"University of Perugia , , ,","place":["Perugia, Italy, 06123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Libera","sequence":"additional","affiliation":[{"name":"University of Perugia , , ,","place":["Perugia, Italy, 06123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6096-3544","authenticated-orcid":true,"given":"Jussara","family":"Amato","sequence":"additional","affiliation":[{"name":"University of Naples Federico II , , ,","place":["Naples, Italy, 80131"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7716-9010","authenticated-orcid":true,"given":"Bruno","family":"Pagano","sequence":"additional","affiliation":[{"name":"University of Naples Federico II , , ,","place":["Naples, Italy, 80131"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5160-6844","authenticated-orcid":true,"given":"Lucia","family":"Comez","sequence":"additional","affiliation":[{"name":"CNR\u2500Istituto Officina dei Materiali (IOM) , ,","place":["Perugia, Italy, 06123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3952-1634","authenticated-orcid":true,"given":"Alessandro","family":"Paciaroni","sequence":"additional","affiliation":[{"name":"University of Perugia , , ,","place":["Perugia, Italy, 06123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Lupi","sequence":"additional","affiliation":[{"name":"Universita\u0300 Roma Tre , , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8367-0610","authenticated-orcid":true,"given":"Cristiano","family":"De Michele","sequence":"additional","affiliation":[{"name":"University of Rome La Sapienza , , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,29]]},"reference":[{"key":"2026091409070457000_cit1","doi-asserted-by":"publisher","first-page":"3452","DOI":"10.1111\/j.1742-4658.2010.07758.x","article-title":"Structure,\nlocation and interactions of G-quadruplexes","volume":"277","author":"Huppert","year":"2010","journal-title":"FEBS J."},{"key":"2026091409070457000_cit2","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.sbi.2006.05.011","article-title":"DNA architecture:\nfrom G to Z","volume":"16","author":"Phan","year":"2006","journal-title":"Curr. 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