Insights into stabilizing weak interactions in designed peptide beta-hairpins.

beta-Hairpin peptides (two anti-parallel strands linked by a reverse beta-turn) have emerged as the simplest systems for probing weak interactions in beta-sheet folding. We describe a model 16-residue hairpin system (peptide beta1: KKYTVSINGKKITVSI) designed around the anti-parallel beta-sheet DNA binding motif of the Met repressor dimer in which two beta-strand sequences are linked through an Asn-Gly type I' beta-turn. The peptide is significantly folded in aqueous solution and has a well-defined conformation as evident from an abundance of NOE data. We review a number of analogues of beta1 designed to estimate the energetic contribution of electrostatic (ion pairing) interactions to hairpin stability, to examine effects of cooperativity and preorganization in determining the energetics of weak interactions, and examine the effects on stability and conformation of incorporation of a three-histidine motif on one face of the hairpin capable of zinc complexation.