STABILIZATION OF A BETA-HAIRPIN CONFORMATION IN A CYCLIC PEPTIDE USING THE TEMPLATING EFFECT OF A HETEROCHIRAL DIPROLINE UNIT

A straightforward and effective method of stabilizing a P-hairpin conf ormation 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 P-hairpin loop was grafted from the extracellular inte rferon gamma receptor onto the heterochiral D-Pro-L-Pro dipeptide temp late to afford a fourteen-residue cyclic peptide. The residues directl y attached to the D-Pro-L-Pro template are shown by NMR spectroscopy t o structurally mimic corresponding residues in adjacent antiparallel b eta-strands in the receptor. MD Simulations with and without time-aver aged distance restraints support this view and indicate that the tip o f 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 fo urteen-residue linear peptide precursor, suggesting that a wide variet y of related protein loop mimetics incorporating the D-Pro-L-Pro templ ate might be readily accessible.