Helix Nucleation by the Smallest Known α‐Helix in Water |
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Authors: | Dr Huy N Hoang Dr Russell W Driver Dr Renée L Beyer Dr Timothy A Hill Dr Aline D?de?Araujo Dr Fabien Plisson Dr Rosemary S Harrison Lena Goedecke Dr Nicholas E Shepherd Prof David P Fairlie |
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Institution: | Division of Chemistry and Structural Biology and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia |
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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. |
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Keywords: | circular dichroism cyclic peptides helical structures helix nucleation NMR spectroscopy |
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