title: Prevention of peptide fibril formation in an aqueous environment by mutation of a single residue to Aib.
abstract: The behavior of a number of 16 residue polypeptides with a sequence Acetyl-EACARXZAACEAAARQ-amide, where X = V or A and Z = A or Aib, is studied under aqueous conditions. It is shown that the substitution of a single alanine residue by alpha-aminoisobutyric acid (Aib) completely alters both the conformation and the aggregation properties of the peptides. The Ala-Ala (X,Z = A,A) peptide is shown by circular dichroism and FTIR methods to adopt a predominately beta-sheet conformation. Furthermore, the peptide has limited solubility and is shown to form fibrils by electron microscopy and thioflavin T binding assays. In contrast, a single substitution at the center of peptide of alanine to Aib (X,Z = A,Aib) completely abolishes fibril formation and alters the conformation to a mixture of random coil and alpha-helix. The results show that Aib is a strong beta-sheet disrupter that is also able to adopt a helical conformation. This is linked to its role in peptaibol antibiotics. Aib provides an attractive alternative to proline and other substitutions in producing peptide variants with a lower tendency to produce fibril aggregates.
authors.affiliation: Department of Chemistry, University of Toronto, Ontario, Canada.
authors.forename: Janet R
authors.initials: JR
authors.lastname: Kumita
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Weston
authors.forename: Lin-P'ing
authors.initials: LP
authors.lastname: Choo-Smith
authors.forename: G Andrew
authors.initials: GA
authors.lastname: Woolley
authors.forename: Oliver S
authors.initials: OS
authors.lastname: Smart
mesh_terms: D000621:Aminoisobutyric Acids / Q000378:metabolism; D002942:Circular Dichroism; D009154:Mutation; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000621:Aminoisobutyric Acids; D010455:Peptides; C100049:2-aminoisobutyric acid