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

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 CαH and residue 9 CO groups. The
structures of peptides 3 and 4, which lack the pro R hydrogen at the Cα 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 αL 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 αR conformation, while LVal(7) in 4 adopts an αL 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.