PT  - JOURNAL ARTICLE
AU  - A. Escobedo
AU  - J. Piccirillo
AU  - J. Aranda
AU  - T. Diercks
AU  - B. Topal
AU  - M. Biesaga
AU  - L. Staby
AU  - B. B. Kragelund
AU  - J. García
AU  - O. Millet
AU  - M. Orozco
AU  - M. Coles
AU  - R. Crehuet
AU  - X. Salvatella
TI  - A glutamine-based single ɑ-helix scaffold to target globular proteins
AID  - 10.1101/2022.05.06.490931
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.05.06.490931
4099  - http://biorxiv.org/content/early/2022/05/06/2022.05.06.490931.short
4100  - http://biorxiv.org/content/early/2022/05/06/2022.05.06.490931.full
AB  - The binding of intrinsically disordered proteins to globular ones often requires the folding of motifs into ɑ-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 ɑ-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 ɑ-helices for a wide range of applications in protein engineering and drug design.Competing Interest StatementThe authors have declared no competing interest.