Designed β-hairpin peptides with defined tight turn stereochemistry

Abstract

The conformational analysis of two synthetic octapeptides, Boc-Leu-Val-Val-D-Pro-L-Ala-Leu-Val-Val-OMe (1) and Boc-Leu-Val-Val-D-Pro-D-Ala-Leu-Val-Val-OMe (2) has been carried out in order to investigate the effect of β-turn stereochemistry on designed β-hairpin structures. Five hundred megahertz ¹H NMR studies establish that both peptides 1 and 2 adopt predominantly β-hairpin conformations in methanol solution. Specific nuclear Overhauser effects provide evidence for a type II′ β-turn conformation for the D-Pro-L-Ala segment in 1, while the NMR data suggest that the type I D-Pro-D-Ala β-turn conformation predominates in peptide 2. Evidence for a minor conformation in peptide 2, in slow exchange on the NMR time scale, is also presented. Interstrand registry is demonstrated in both peptides 1 and 2. The crystal structure of 1 reveals two independent molecules in the crystallographic asymmetric unit, both of which adopt β-hairpin conformations nucleated by D-Pro-L-Ala type II′ β-turns and are stabilized by three cross-strand hydrogen bonds. CD spectra for peptides 1 and 2 show marked differences, presumably as a consequence of the superposition of spectral bands arising from both β-turn and β-strand conformations.