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Mixed chirality alpha helixv2.pdf (7.08 MB)

Mixed Chirality α-Helix in a Stapled Bicyclic and a Linear Antimicrobial Peptide Revealed by X-Ray Crystallography

revised on 05.03.2021, 15:24 and posted on 08.03.2021, 07:54 by stéphane Baeriswyl, Hippolyte Personne, Ivan Di Bonaventura, Thilo Köhler, Christian van Delden, Achim Stocker, Sacha Javor, Jean-Louis Reymond

The peptide α-helix is right-handed when containing amino acids with L-chirality, and left-handed with D-chirality. What happens in between is largely unknown, however α-helices have not been reported with mixed chirality sequences unless a strong non-natural helix inducer such as amino-isobutyric acid was used. Herein we report the discovery of a membrane disruptive amphiphilic antimicrobial undecapeptide containing seven L- and four D-residues forming a stable right-handed α-helix in stapled bicyclic and linear forms. The α-helical fold is evidenced by X-ray crystallography and supported in solution by circular dichroism spectra as well as molecular dynamics simulations. The linear mixed chirality peptide is as active as the L-sequence against multidrug resistant bacteria but shows no hemolysis and full stability against serum proteolysis. Searching for mixed chirality analogs preserving folding might be generally useful to optimize α-helical bioactive peptides.


Swiss National Science Foundation Grant no. 200020_178998

Swiss National Science Foundation Grant no. 407240_167048



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University of Bern



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no conflict of interest