Conformations of heterochiral and homochiral proline-pseudoproline segments in peptides: context dependent cis-trans peptide bond isomerization

Abstract

The pseudoproline residue (ψPro, L-2,2-dimethyl-1,3-thiazolidine-4-carboxylic acid) has been introduced into heterochiral diproline segments that have been previously shown to facilitate the formation of β-hairpins, containing central two and three residue turns. NMR studies of the octapeptide Boc-Leu-Phe-Val-^DPro-ψPro-Leu-Phe-Val-OMe (1), Boc-Leu-Val-Val-^DPro-ψPro-Leu-Val-Val-OMe (2), and the nonapeptide sequence Boc-Leu-Phe-Val-^DPro-ψPro-^DAla-Leu-Phe-Val-OMe (3) established well-registered β-hairpin structures in chloroform solution, with the almost exclusive population of the trans conformation for the peptide bond preceding the ?Pro residue. The β-hairpin conformation of 1 is confirmed by single crystal X-ray diffraction. Truncation of the strand length in Boc-Val-^DPro-ψPro-Leu-OMe (4) results in an increase in the population of the cis conformer, with a cis/trans ratio of 3.65. Replacement of ψPro in 4 by ^LPro in 5, results in almost exclusive population of the trans form, resulting in an incipient β-hairpin conformation, stabilized by two intramolecular hydrogen bonds. Further truncation of the sequence gives an appreciable rise in the population of cis conformers in the tripeptide Piv-^DPro-ψPro-Leu-OMe (6). In the homochiral segment Piv-Pro-ψPro-Leu-OMe (7) only the cis form is observed with the NMR evidence strongly supporting a type VIa β-turn conformation, stabilized by a 4→1 hydrogen bond between the Piv (CO) and Leu (3) NH groups. The crystal structure of the analog peptide 7a (Piv-Pro-ψ^H,CH3Pro-Leu-NHMe) confirms the cis peptide bond geometry for the Pro-ψ^H,CH3Pro peptide bond, resulting in a type VIa β-turn conformation.