3 years ago

Rational Design of Membrane-Pore-Forming Peptides

Rational Design of Membrane-Pore-Forming Peptides
Gernot Posselt, Max Pillong, Silja Wessler, Claudia S. Neuhaus, Petra Schneider, Jan A. Hiss, Markus Blatter, Yen-Chu Lin, Simon Bachler, Gisbert Schneider, Karl-Heinz Altmann, Alex T. Müller, Petra S. Dittrich, Bernhard Pfeiffer
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. Peptides with desired properties and biological activities are automatically generated by a new computational approach. Their anticipated mode of action can be confirmed by biochemical and biophysical analyses. The design algorithm leads to the discovery of novel peptides with increased biological activities, surpassing the efficacy of the natural paragon.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/smll.201701316

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