Combinatorial Approaches: A New Tool to Search for Highly Structured β-Hairpin Peptides

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-01, Vol.99 (2), p.614-619
• Main Authors: Pastor, Maria Teresa, de la Paz, Manuela López, Lacroix, Emmanuel, Serrano, Luis, Pérez-Payá, Enrique
• Format: Article
• Language: English
• Subjects: Aggregation; Amino Acid Sequence; Amino acids; Biochemistry; Biological Sciences; Chemical equilibrium; Circular Dichroism; Combinatorial Chemistry Techniques; Dichroism; Drug Design; Libraries; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Sequence Data; Pastors; Peptide Library; Peptides; Peptides - chemical synthesis; Peptides - chemistry; Population parameters; Population structure; Protein Folding; Protein Structure, Secondary; Scaffolds
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.012583999

Here we present a combinatorial approach to evolve a stable β-hairpin fold in a linear peptide. Starting with a de novo-designed linear peptide that shows a β-hairpin structure population of around 30%, we selected four positions to build up a combinatorial library of 204sequences. Deconvolution of the library using circular dichroism reduced such a sequence complexity to 36 defined sequences. Circular dichroism and NMR of these peptides resulted in the identification of two linear 14-aa-long peptides that in plain buffered solutions showed a percentage of β-hairpin structure higher than 70%. Our results show how combinatorial approaches can be used to obtain highly structured peptide sequences that could be used as templates in which functionality can be introduced.