Conformational preferences of peptides containing reverse-turn mimetic bicyclic lactams: Inverse gamma-turns versus type-II ' beta-turns - Insights into beta-hairpin stability

The solid-phase synthesis and characterization of a series of peptides (3-9 ), containing reverse-turn mimetic bicyclic lactams (1a, 1b), was reported in the preceding paper. The bicyclic lactams (1a, 1b) possess high structur al similarity to the two central residues of a beta-turn. The conformationa l preferences of the constrained peptides have been investigated by NMR spe ctroscopy and IR spectroscopy. Our experimental results have been complemen ted by computer modelling studies and show that the constrained peptides (3 -9) form an inverse gamma-turn or a type-II' beta-turn through intramolecul ar hydrogen bonding, depending on the nature of the reverse-turn mimic. In N-acetylated tetrapeptide mimics incorporating the two different bicyclic l actams (a series and b series), H-5 is available for either a gamma-turn (7 -membered ring with the carbonyl group of the bicyclic lactam) or a beta-tu rn (10-membered ring with the carbonyl group of residue 2), as shown in Fig ures 7 and 9. The a series incorporating the (5,7)-bicyclic lactam predomin antly induces the gamma-turn conformation, while the b series incorporating the (5,6)-bicyclic lactam can promote either a gamma-turn or a beta-turn c onformation, with the beta-turn usually being preferred and with varying de grees of beta-hairpin formation.