Helix Nucleation by the Smallest Known α-Helix in Water.

Hoang, Huy N.; Driver, Russell W.; Beyer, Renée L.; Hill, Timothy A.; de Araujo, Aline D.; Plisson, Fabien; Harrison, Rosemary S.; Goedecke, Lena; Shepherd, Nicholas E.; Fairlie, David P.

Cyclic pentapeptides (e.g. Ac-(cyclo-1,5)- [KAXAD]-NH2; X=Ala, 1; Arg, 2) in water adopt one ahelical turn defined by three hydrogen bonds. NMR structure analysis reveals a slight distortion from a-helicity at the Cterminal 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 a-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.

NUCLEATION; PEPTIDE analysis; PROTEIN-protein interactions; LACTAMS; CHEMICAL synthesis; HYDROGEN bonding

Angewandte Chemie International Edition, 2016, Vol 55, Issue 29, p8275

1433-7851

Academic Journal

10.1002/anie.201602079