Puckering effects of 4-hy­droxy-l-proline isomers on the conformation of ornithine-free Gramicidin S

Abstract

The structures of Orn-free Gramicidin S with cis/trans-isomers of Hyp were solved, and the puckering of Hyp was unexpectedly down in both isomers.

The cyclic peptide cyclo(Val-Leu-Leu-d-Phe-Pro)₂ (peptide 1) was specifically designed for structural chemistry investigations, drawing inspiration from Gramicidin S (GS). Previous studies have shown that Pro residues within 1 adopt a down-puckering conformation of the pyrrolidine ring. By incorporating fluoride-Pro with 4-trans/cis-isomers into 1, an up-puckering conformation was successfully induced. In the current investigation, introducing hy­droxy­prolines with 4-trans/cis-isomer configurations (tHyp/cHyp) into 1 gave cyclo(Val-Leu-Leu-d-Phe-tHyp)₂ methanol disolvate monohydrate, C₆₂H₉₄N₁₀O₁₂·2CH₄O·H₂O (4), and cyclo(Val-Leu-Leu-d-Phe-cHyp)₂ monohydrate, C₆₂H₉₄N₁₀O₁₂·H₂O (5), respectively. However, the puckering of 4 and 5 remained in the down conformation, regardless of the geometric position of the hydroxyl group. Although the backbone structure of 4 with trans-substitution was asymmetric, the asymmetric backbone of 5 with cis-substitution was unexpected. It is speculated that the anti­cipated influence of stress from the geometric positioning, which was expected to affect the puckering, may have been mitigated by inter­actions between the hydroxyl groups of hy­droxy­proline, the solvent mol­ecules, and peptides.