An Improved Turn Structure for Inducing β‐Hairpin Formation in Peptides
Xingyue Li, Andrew L. Sabol, Michał Wierzbicki, Patrick J. Salveson, James S. Nowick
Abstract
Abstract Although β‐hairpins are widespread in proteins, there is no tool to coax any small peptide to adopt a β‐hairpin conformation, regardless of sequence. Here, we report that δ‐linked γ( R )‐methyl‐ornithine ( δ MeOrn) provides an improved β‐turn template for inducing a β‐hairpin conformation in peptides. We developed a synthesis of protected δ MeOrn as a building block suitable for use in Fmoc‐based solid‐phase peptide synthesis. The synthesis begins with l ‐leucine and affords gram quantities of the N α ‐Boc‐ N δ ‐Fmoc‐γ( R )‐methyl‐ornithine building block. X‐ray crystallography confirms that the δ MeOrn turn unit adopts a folded structure in a macrocyclic β‐hairpin peptide. CD and NMR spectroscopy allow comparison of the δ MeOrn turn template to the δ‐linked ornithine ( δ Orn) turn template that we previously introduced and to the popular d ‐Pro‐Gly turn template. These studies show that the folding of the δ MeOrn turn template is substantially better than that of δ Orn and is comparable to d ‐Pro‐Gly.