Stereochemistry of linking segments in the design of helix–helix motifs in peptides. Crystallographic comparison of a glycyl–dipropylglycyl–glycyl segment in a tripeptide and a 14-residue peptide

Abstract

As part of a program to develop synthetic helix–linker–helix peptides the conformational properties of various linking segments are currently being investigated. The propensity of α,α-di-n-propylglycine (Dpg) residues to adopt backbone conformations in the extended region of the Ramachandran map, suggested by theoretical calculations and supported by experimental observations, prompted us to investigate the utility of the Gly-Dpg-Gly segment as a rigid linking motif. The crystal structure of the achiral tripeptide Boc-Gly-Dpg-Gly-OH 1 revealed a fully extended conformation (ϕ = ±178°, ψ = ±171°) at Dpg(2), with Gly(1) adopting a helical conformation (ϕ = +-72 °, ψ = +-32 °). The addition of flanking helical segments in the 14 residue peptide Boc-Val-Val-Ala-Leu-Gly-Dpg-Gly-Val-Ala-Leu-Aib-Val-Ala-Leu-OMe 2 resulted in the crystallographic characterization of a continuous helix over the entire length of the peptide. Peptide 1 crystallized in the centrosymmetric space group P2₁/c with a = 9.505(2) Å, b = 11.025(2) Å, c = 20.075(4) Å, β = 90.19° and Z = 4. Peptide 2 crystallized in space group P2₁2₁2₁ with a = 10.172(1) Å, b = 17.521(4) Å, c = 46.438(12) Å and Z = 4. A comparative analysis of Gly-Dpg-Gly segments from available crystal structures indicates a high conformational variability of this segment. This analysis suggests that context and environment may be strong conformational determinants for the Gly-Dpg-Gly segment.