The design of bioactive peptides is currently undergoing a renaissance, spurred in parts by the need for new tool compounds in chemical biology and medicinal chemistry. There is sustained potential of advanced computational methods for designing peptides with the desired activity [1]. We will present and discuss unsupervised and supervised machine-learning approaches to capture sequence-activity relationships from limited training sets, and demonstrate the practical applicability of these models for the de novodesign of potent membrane-active peptides, specifically new helical antimicrobial peptides [2]. The results suggest a direct relationship between membrane binding and the peptides' environment-sensitive, inducible helical structure. Thermal analysis revealed entropy-driven mechanisms of action of the designer peptides. We will also present the concept of 'peptide morphing', i.e. the systematic transformation of a seed peptide into a target sequence based on a probabilistic amino acid similarity model. The method mimics an evolutionary strategy for physicochemically motivated peptide alteration based on physicochemical residue similarity [4]. Finally, we will present our recent studies on the design of new peptides binding to MHC-I molecules, for which we employed an ant colony optimization method for amino acid sequence design [3,4]. [1] Schneider, G., Lin, Y.-C., Koch, C. P., Pillong, M., Perna, A. M., Reutlinger, M., Hiss, J. A. Chimia 2013  , 67, 859-863.[2] Fjell, C. D., Hiss, J. A., Hancock, R. E. W., Schneider, G. Nat. Rev. Drug Discov. 2012  , 11, 37-51.[3] Koch, C. P., Perna, A. M., Weissm�ller, S., Bauer, S., Pillong, M., Baleeiro, R. B., Reutlinger, M., Folkers, G., Walden, P., Wrede, P., Hiss, J. A., Waibler, Z., Schneider, G. ACS Chem. Biol. 2013  , 8, 1876-1881.[4] Hiss, J. A., Reutlinger, M., Koch, C. P., Perna, A. M., Schneider, P., Rodrigues, T., Haller, S., Folkers, G., Weber, L., Baleeiro, R. B., Walden, P., Wrede, P., Schneider, G. Future Med. Chem. 2014  , 6, 267-280.

Peptide design reloaded

248th National Meeting (2014)

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