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Through comprehensive calorimetric as well as high-resolution NMR structural studies, Q\u2013D junctions with a hairpin-type snapback loop coaxially stacked onto an outer G-tetrad were identified to be most effective binding sites for various polycyclic quadruplex ligands. The Q\u2013D interface is readily recognized by intercalation of the ligand aromatic core structure between G-tetrad and the neighboring base pair. Based on the thermodynamic and structural data, guidelines for the design of ligands with enhanced selectivity towards a Q\u2013D interface emerge. Whereas intercalation at Q\u2013D junctions mostly outcompete stacking at the quadruplex free outer tetrad or intercalation between duplex base pairs to varying degrees, ligand side chains considerably contribute to the selectivity for a Q\u2013D target over other binding sites. In contrast to common perceptions, an appended side chain that additionally interacts within the duplex minor groove may confer only poor selectivity. Rather, the Q\u2013D selectivity is suggested to benefit from an extension of the side chain towards the exposed part of the G-tetrad at the junction. The presented results will support the design of selective high-affinity binding ligands for targeting Q\u2013D interfaces in medicinal but also technological applications.<\/jats:p>","DOI":"10.1093\/nar\/gkac1088","type":"journal-article","created":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T11:16:58Z","timestamp":1669202218000},"page":"11948-11964","source":"Crossref","is-referenced-by-count":28,"title":["High-affinity binding at quadruplex\u2013duplex junctions: rather the rule than the exception"],"prefix":"10.1093","volume":"50","author":[{"given":"Yoanes Maria","family":"Vianney","sequence":"first","affiliation":[{"name":"Institute of Biochemistry, Universit\u00e4t Greifswald , Felix-Hausdorff-Str. 4, D-17489 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2736-6606","authenticated-orcid":false,"given":"Klaus","family":"Weisz","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Universit\u00e4t Greifswald , Felix-Hausdorff-Str. 4, D-17489 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,23]]},"reference":[{"key":"2022120608382570900_B1","doi-asserted-by":"crossref","first-page":"5402","DOI":"10.1093\/nar\/gkl655","article-title":"Quadruplex DNA: sequence, topology and structure","volume":"34","author":"Burge","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"2022120608382570900_B2","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.trechm.2019.07.002","article-title":"The structure and function of DNA G-quadruplexes","volume":"2","author":"Spiegel","year":"2020","journal-title":"Trends Chem"},{"key":"2022120608382570900_B3","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrd3428","article-title":"Targeting G-quadruplexes in gene promoters: a novel anticancer strategy?","volume":"10","author":"Balasubramanian","year":"2011","journal-title":"Nat. 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