Enhancing the binding of the β-sheet breaker peptide LPFFD to the amyloid-β fibrils by aromatic modifications: A molecular dynamics simulation study.

Alzheimer's is a fatal neurodegenerative disease for which there is no cure at present. The disease is characterized by the presence of plaques in the brains of a patient, which are composed mainly of aggregates of the amyloid-β peptide in the form of β-sheet fibrils. Here, we investigated the possibility of exploiting the superior binding ability of aromatic amino acids to a particular model of the amyloid-β fibrils. which is a difficult target for drug design. The β-sheet breaker peptide LPFFD was modified with aromatic amino acids and its binding to these fibrils was studied. We found that the orientation and the electrostatic complementarity of the modified peptide with respect to the fibrils played a crucial role in determining whether its binding was improved by the aromatic amino acids. The modified LPFFD peptides were able to bind to those fibril residues. which are important in the aggregation of amyloid-β peptides and thus can potentially inhibit the further aggregation of the amyloid-beta peptides by blocking their interactions. We found that the tryptophan modified LPFFD peptides had the best binding affinities. In most cases, the aromatic amino acids in the N-terminus of the modified peptides made more contacts with the fibrils than those in the C-terminus. We also found that increasing the aromatic content did not significantly improve the binding of the LPFFD peptide to the fibrils. Our study can serve as a basis for the design of novel peptide-based drugs for Alzheimer's disease in which aromatic interactions play an important role.