De novo design of conformationally flexible transmembrane peptides driving membrane fusion

Mathias W. Hofmann, Katrin Weise, Julian Ollesch, Prashant Agrawal, Holger Stalz, Walter Stelzer, Frans Hulsbergen, Huub De Groot, Klaus Gerwert, Jennifer Reed, Dieter Langosch

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


Fusion of biological membranes is mediated by distinct integral membrane proteins, e.g., soluble N-ethylmaleimide-sensitive factor attachment protein receptors and viral fusion proteins. Previous work has indicated that the transmembrane segments (TMSs) of such integral membrane proteins play an important role in fusion. Furthermore, peptide mimics of the transmembrane part can drive the fusion of liposomes, and evidence had been obtained that fusogenicity depends on their conformational flexibility. To test this hypothesis, we present a series of unnatural TMSs that were designed de novo based on the structural properties of hydrophobic residues. We find that the fusogenicity of these peptides depends on the ratio of α-helix-promoting Leu and β-sheet-promoting Val residues and is enhanced by helix-destabilizing Pro and Gly residues within their hydrophobic cores. The ability of these peptides to refold from an α-helical state to a β-sheet conformation and backwards was determined under different conditions. Membrane fusogenic peptides with mixed Leu/Val sequences tend to switch more readily between different conformations than a nonfusogenic peptide with an oligo-Leu core. We propose that structural flexibility of these TMSs is a prerequisite of fusogenicity.

Original languageEnglish
Pages (from-to)14776-14781
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number41
StatePublished - 12 Oct 2004


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