POLYALANINE-BASED PEPTIDES AS MODELS FOR SELF-ASSOCIATED BETA-PLEATED-SHEET COMPLEXES

The occurrence of beta-sheet motifs in a number of neurodegenerative d isorders has brought about the need for the de novo design of soluble model beta-sheet complexes. Such model complexes are expected to furth er the understanding of the interconversion processes that occur from cellular allowed random coil or alpha-helical conformation into insolu ble cell-deleterious beta-pleated-sheet motifs. In the present study, polyalanine-based peptides (i.e., derived from Ac-KA(14)K-NH2) were de signed that underwent conformational changes from monomeric random coi l conformations into soluble, macromolecular beta-pleated-sheet comple xes without any covalent modification. The interconversion was found t o be length-, environment-, and concentration-dependent and to be driv en by hydrophobic interactions between the methyl groups of the alanin e side chains. A series of substitution analogs of Ac-KA(14)K-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 beta-sheet complexes.