Helix Nucleation by the Smallest Known α‐Helix in Water

Abstract

Cyclic pentapeptides (e.g. Ac‐(cyclo‐1,5)‐[KAXAD]‐NH2; X=Ala, 1; Arg, 2) in water adopt one α‐helical turn defined by three hydrogen bonds. NMR structure analysis reveals a slight distortion from α‐helicity at the C‐terminal aspartate caused by torsional restraints imposed by the K(i)–D(i+4) lactam bridge. To investigate this effect on helix nucleation, the more water‐soluble 2 was appended to N‐, C‐, or both termini of a palindromic peptide ARAARAARA (≤5 % helicity), resulting in 67, 92, or 100 % relative α‐helicity, as calculated from CD spectra. From the C‐terminus of peptides, 2 can nucleate at least six α‐helical turns. From the N‐terminus, imperfect alignment of the Asp5 backbone amide in 2 reduces helix nucleation, but is corrected by a second unit of 2 separated by 0–9 residues from the first. These cyclic peptides are extremely versatile helix nucleators that can be placed anywhere in 5–25 residue peptides, which correspond to most helix lengths in protein–protein interactions.

The key position: influence of staple location on constrained peptide conformation and binding

“…It is possible that the presence of the lactam amide functional group might be influencing residue i+4 secondary shifts and temperature coefficients, however the downfield shifted NH suggests a deshielding effect of the lactam, while the unusually large and negative NH temperature coefficient is more consistent with a shielding effect from this group 27 . Similar effects on linker αH and temperature coefficients were found for constrained peptides studied by Hoang et al 28 . These were attributed to local distortion of the helical structure, however no such distortion was evident in the NMR structures calculated for our integrin-derived peptides.…”

Design and structural characterisation of monomeric water-soluble α-helix and β-hairpin peptides: State-of-the-art

“…Finally, it should be mentioned that a cyclic peptapeptide (Ac-(cyclo-1,5)-[KAXAD]-NH 2 ; X=Ala or Arg) has been recently reported as the shortest peptide able to be αhelical in water [193]. It is stabilised by a (i, i+4) lactam bridge between the side chains of Lys and Asp, and likely to have the N-and C-termini protected contributes to its stability.…”

Chiral Sulfoxide-Induced Single Turn Peptide α-Helicity

“…Over the past several decades, various approaches, spanning non-covalent and covalent strategies, to reinforcing the bioactive helical conformation were developed17. Various non-covalent strategies have been used to stabilize peptide backbone toward the a-helical conformation, including helix-nucleating templates18192021 and introducing α, α-disubstituted amino acid, such as aminoisobutyric acid2223. While for covalent strategies, a common approach for inducing and stabilizing fixed secondary structure in peptides is by tethering two side chains on the same face of the helix via different cross-links.…”