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

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 alpha-helix in water. The origin of the stabilization is unclear. The observed dependence of alpha-helicity on the solvent and cyclization linker led us to discover a novel long-range n to pi* 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 pi* CO...C-gamma=omicron interaction uniquely enforces an almost perfect and remarkably stable peptide alpha-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.