Polyalanine-Based Peptides as Models for Self-Associated β-Pleated-Sheet Complexes

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Abstract
The occurrence of β-sheet motifs in a number of neurodegenerative disorders has brought about the need for the de novo design of soluble model β-sheet complexes. Such model complexes are expected to further the understanding of the interconversion processes that occur from cellular allowed random coil or α-helical conformation into insoluble cell-deleterious β-pleated-sheet motifs. In the present study, polyalanine-based peptides (i.e., derived from Ac-KA14K-NH2) were designed that underwent conformational changes from monomeric random coil conformations into soluble, macromolecular β-pleated-sheet complexes without any covalent modification. The interconversion was found to be length-, environment-, and concentration-dependent and to be driven by hydrophobic interactions between the methyl groups of the alanine side chains. A series of substitution analogs of Ac-KA14K-NH2 was used to study the amino acid acceptability within the hydrophobic core of the complex, as well as at both termini. The formation of amyloid plaques in a number of amyloidogenic peptides could be related to the presence of amino acids within their sequences that were found to have a high propensity to occur in these model β-sheet complexes.