Stabilization of aβ-Hairpin Conformation in a Cyclic Peptide Using the Templating Effect of a Heterochiral Diproline Unit

A straightforward and effective method of stabilizing a β-hairpin conformation in a cyclic protein loop mimetic is described, which exploits the templating effect of a heterochiral D-Pro-L-Pro dipeptide unit. A twelve-residue β-hairpin loop was grafted from the extracellular interferon γ receptor onto the heterochiral D-Pro-L-Pro dipeptide template to afford a fourteen-residue cyclic peptide. The residues directly attached to the D-Pro-L-Pro template are shown by NMR spectroscopy to structurally mimic corresponding residues in adjacent antiparallel β-strands in the receptor. MD Simulations with and without time-averaged distance restraints support this view and indicate that the tip of the loop is more flexible, as inferred also for the receptor protein from crystallographic data. The templating effect of the heterochiral diproline unit also promotes efficient backbone cyclization of the fourteen-residue linear peptide precursor, suggesting that a wide variety of related protein loop mimetics incorporating the D-Pro-L-Pro template might be readily accessible.