A single-residue substitution inhibits fibrillization of Ala-based pentapeptides. A spectroscopic and molecular dynamics investigation.

The aggregation properties of two Ala-based pentapeptides were investigated by spectroscopic techniques and molecular dynamics (MD) simulations. The two peptides{,} both functionalized at the N-terminus with a pyrenyl group{,} differ for the insertion of an ?-aminoisobutyric acid residue at position 4. We showed that this single modification of the homo-peptide sequence inhibits the aggregation of the pentapeptide in aqueous solutions. Atomic force microscopy imaging revealed that the two peptides form mesoscopic aggregates of very different morphology when deposited on mica. MD experiments showed that the two peptides have a very different propensity to form [small beta]-pleated sheet structures{,} as confirmed by our spectroscopic measurements. The implications of these findings to our understanding of the mechanism leading to the formation of amyloid structures{,} primary responsible for numerous neurodegenerative diseases{,} are also discussed.