BPS2026 – Inhibition of the amyloid β protein aggregation with polyphenol drugs using computational chemistry

Alzheimer’s disease is a neurodegenerative disorder affecting nearly 7 million Americans, and that number increases yearly. A commonality among Alzheimer’s patients is the presence of amyloid plaques in the brain. These plaques contain high concentrations of 42-amino acid long amyloid β peptides. These peptides arrange in double horseshoe β-sheet structures which allows them to stabilize in the brain and contribute to the progression of Alzheimer’s disease. Alzheimer’s disease is currently being heavily researched as it is the leading cause for dementia; however there is currently no cure available, only preventative treatments. Naturally occurring polyphenols appear to be promising inhibitors of this aggregation in its formation stages due to their hydrophobic and antioxidant properties. Our current study uses multiple computational chemistry methods that mimic in vitro conditions. Molecular docking is employed to find the most favorable bound conformation of each polyphenol, or multiple polyphenols at elevated concentrations. Molecular dynamics uses the docked locations of the ligands to generate simulations that investigate the interactions between the polyphenol ligand and the amyloid β protein on a microsecond time scale. The simulations are then analyzed to study disaggregation of the amyloid β protein. We investigated four different polyphenols and simulated them each at four different concentrations (ranging from 2–30 mM) to 5,000 ns to capture interactions with an amyloid β aggregate. These increased concentrations allow us to view what interactions may occur between the protein and ligands over a longer period of time, while still only simulating to 5,000 ns. Our simulations reveal significant differences in binding affinity and disruption ofβ-sheet stability among the tested polyphenols, linked to their structural differences. These findings advance our understanding of polyphenols as potential Alzheimer’s treatments.