A Novel Long‐Range n to π* Interaction Secures the Smallest known α‐Helix in Water.

Hoang, Huy N.; Wu, Chongyang; Hill, Timothy A.; Dantas de Araujo, Aline; Bernhardt, Paul V.; Liu, Ligong; Fairlie, David P.

The introduction of an amide bond linking side chains of the first and fifth amino acids forms a cyclic pentapeptide that optimally stabilizes the smallest known α‐helix in water. The origin of the stabilization is unclear. The observed dependence of α‐helicity on the solvent and cyclization linker led us to discover a novel long‐range n to π* interaction between a main‐chain amide oxygen and a uniquely positioned carbonyl group in the linker of cyclic pentapeptides. CD and NMR spectra, NMR and X‐ray structures, modelling, and MD simulations reveal that this first example of a synthetically incorporated long‐range n to π* CO⋅⋅⋅Cγ=Ο interaction uniquely enforces an almost perfect and remarkably stable peptide α‐helix in water but not in DMSO. This unusual interaction with a covalent amide bond outside the helical backbone suggests new approaches to synthetically stabilize peptide structures in water.

CYCLIC groups; CARBONYL group; COVALENT bonds; WATER; AMINO acids

Angewandte Chemie, 2019, Vol 131, Issue 52, p19049

0044-8249

Academic Journal

10.1002/ange.201911277