Role of hydrophobic clusters in the stability of alpha-helical coiled coils and their conversion to amyloid-like beta-sheets.
We designed a library of short peptides using standard rules for coiled-coil assembly. Depending on the composition of amino acids in the non-interacting region of the coiled coil (positions b, c, and f) these peptides are able to convert from alpha-helical to beta-sheet secondary structure. This type of transition is observed in amyloid-like proteins and is a key feature associated with many types of neurodegenerative diseases. Studies on peptides that are 14 amino acids in length indicated that positioning hydrophobic amino acids at an f position within a heptad repeat accelerated the rate of conformational conversion as compared to that at a c position. We believe that this occurs because of the formation of a hydrophobic pocket that preferentially stabilizes beta-sheets over alpha-helices. This effect was also observed in longer 21 amino acid peptides. Our study shows that the relative rates of structural conversion correlate with the formation of a continuous three-amino-acid hydrophobic patch consisting of amino acids in the d, f, and a positions and not on the secondary structure propensities of the individual amino acids. The sequence-structure relationship observed in this study will be used to help understand the mechanism of amyloid fiber formation and design future coiled-coil and beta-sheet-forming peptide systems.
Dong
He
H
Departments of Chemistry, 6100 Main Street MS60, Houston, Texas 77005, USA.
Hartgerink
Jeffrey D
JD
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
D000682:Amyloid; D019151:Peptide Library; D010455:Peptides