Probing the role of the C-H···O hydrogen bond stabilized polypeptide chain reversal at the c-terminus of designed peptide helices. Structural characterization of three decapeptides

Abstract

The structural characterization in crystals of three designed decapeptides containing a double d-segment at the C-terminus is described. The crystal structures of the peptides Boc-Leu-Aib-Val-Xxx-Leu-Aib-Val-^DAla-^DLeu-Aib-OMe, (Xxx = Gly 2, ^DAla 3, Aib 4) have been determined and compared with those reported earlier for peptide 1 (Xxx = Ala) and the all l analogue Boc-Leu-Aib-Val-Ala-Leu-Aib-Val-Ala-Leu-Aib-OMe, which yielded a perfect right-handed α-helical structure. Peptides 1 and 2 reveal a right-handed helical segment spanning residues 1 to 7, ending in a Schellman motif with ^DAla(8) functioning as the terminating residue. Polypeptide chain reversal occurs at residue 9, a novel feature that appears to be the consequence of a C-H···O hydrogen bond between residue 4 C^αH and residue 9 CO groups. The structures of peptides 3 and 4, which lack the pro R hydrogen at the C^α atom of residue 4, are dramatically different. Peptide 3 adopts a right-handed helical conformation over the 1 to 7 segment. Residues 8 and 9 adopt α_L conformations forming a C-terminus type I′ β-turn, corresponding to an incipient left-handed twist of the polypeptide chain. In peptide 4, helix termination occurs at Aib(6), with residues 6 to 9 forming a left-handed helix, resulting in a structure that accommodates direct fusion of two helical segments of opposite twist. Peptides 3 and 4 provide examples of chiral residues occurring in the less favored sense of helical twist; ^DAla(4) in peptide 3 adopts an α_R conformation, while ^LVal(7) in 4 adopts an α_L conformation. The structural comparison of the decapeptides reported here provides evidence for the role of specific C-H···O hydrogen bonds in stabilizing chain reversals at helix termini, which may be relevant in aligning contiguous helical and strand segments in polypeptide structures.