Escobedo, AlbertPiccirillo, JonathanAranda, JuanDiercks, TammoMateos, BorjaGarcia-Cabau, CarlaSánchez-Navarro, MacarenaTopal, BusraBiesaga, MateuszStaby, LasseKragelund, Birthe B.García, JesúsMillet, OscarOrozco, ModestoColes, MurrayCrehuet, RamonSalvatella, Xavier2023-01-242023-01-242022Escobedo A, Piccirillo J, Aranda J, Diercks T, Mateos B, Garcia-Cabau C, Sánchez-Navarro M, Topal B, Biesaga M, Staby L, Kragelund BB, García J, Millet O, Orozco M, Coles M, Crehuet R, Salvatella X. A glutamine-based single α-helix scaffold to target globular proteins. Nat Commun. 2022 Nov 18;13(1):7073. DOI: 10.1038/s41467-022-34793-62041-1723http://hdl.handle.net/10230/55410The binding of intrinsically disordered proteins to globular ones can require the folding of motifs into α-helices. These interactions offer opportunities for therapeutic intervention but their modulation with small molecules is challenging because they bury large surfaces. Linear peptides that display the residues that are key for binding can be targeted to globular proteins when they form stable helices, which in most cases requires their chemical modification. Here we present rules to design peptides that fold into single α-helices by instead concatenating glutamine side chain to main chain hydrogen bonds recently discovered in polyglutamine helices. The resulting peptides are uncharged, contain only natural amino acids, and their sequences can be optimized to interact with specific targets. Our results provide design rules to obtain single α-helices for a wide range of applications in protein engineering and drug design.application/pdfeng© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-022-34793-6Biophysical chemistryIntrinsically disordered proteinsPeptidesSolution-state NMRinfo:eu-repo/semantics/openAccess