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

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 alpha,alpha-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 (phi = +/-178 degrees, psi = +/-171 degrees) at Dpg(2), with Gly(1) adopting a helical conformation (phi = -/+72 degrees, psi = -/+32 degrees). 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 P2(1)/c with a = 9.505(2)Angstrom,b = 11.025(2) Angstrom, c= 20.075(4) Angstrom, beta= 90.19 degrees and Z = 4, Peptide 2 crystallized in space group P2(1)2(1)2(1) with a = 10.172(1) Angstrom, b = 17.521(4) Angstrom, c = 46.438(12) Angstrom 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.