Rational Design of Membrane‐Pore‐Forming Peptides

Specific interactions of peptides with lipid membranes are essential for cellular communication and constitute a central aspect of the innate host defense against pathogens. A computational method for generating innovative membrane‐pore‐forming peptides inspired by natural templates is presented. Peptide representation in terms of sequence‐ and topology‐dependent hydrophobic moments is introduced. This design concept proves to be appropriate for the de novo generation of first‐in‐class membrane‐active peptides with the anticipated mode of action. The designed peptides outperform the natural template in terms of their antibacterial activity. They form a kinked helical structure and self‐assemble in the membrane by an entropy‐driven mechanism to form dynamically growing pores that are dependent on the lipid composition. The results of this study demonstrate the unique potential of natural template‐based peptide design for chemical biology and medicinal chemistry.