Prevention of Peptide Fibril Formation in an Aqueous Environment by Mutation of a Single Residue to Aib

The behavior of a number of 16 residue polypeptides with a sequence Acetyl-EACAR XZ AACEAAARQ-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 α-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 β-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 α-helix. The results show that Aib is a strong β-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.