The aggregation of Amyloid β peptides (Aβ) in the brain to form large protein fibrils is recognized as one of the causative events leading to Alzheimer’s Disease (AD). AD is characterized by memory loss and decreased cognitive function as a result of neurodegeneration. Given the centrality of Aβ aggregates to the disease process, perturbation of the aggregation pathway has become a popular target for developing novel pharmacological interventions. Recent in-vitro studies suggest a class of polyphenolic molecules known as biflavonoids can inhibit aggregation and promote disaggregation of the neurotoxic Aβ fibrils. The precise mechanism of small molecular aggregation inhibitors remains poorly understood. Given the limitations of experimental methods, computational modelling has emerged as a valuable tool for studying Aβ-inhibitor interactions in atomistic detail. Here, we used thioflavin T (ThT) fluorescence assays to evaluate the ability of biflavonoid molecules to disaggregate preformed Aβ42 fibrils in vitro. Five biflavonoids with minor structural differences were investigated in the assays. To determine how minor structural variations contribute to observed differences in inhibitor activity, molecular modeling methods were employed to examine potential biflavonoid-Aβ42 fibril interactions on an atomic level. We used an all-atom structure for a disease-relevant polymorph of Aβ42 fibril to model the site-specific binding and disaggregation mechanisms of several biflavonoids. Using the entire fibril surface as a search space, molecular docking simulations were performed to identify optimal binding poses for five biflavonoids. Conformational perturbations to the fibril in complex with these poses were further examined through explicit solvent unrestrained molecular dynamics simulations on the microsecond time-scale. Analysis of these trajectories highlighted specific binding interactions near the N-terminus of the Aβ peptides in the fibril model, and large-scale structural changes occurred on the nanosecond timescale suggesting a mechanism for biflavonoid driven structural remodeling.

Investigation of biflavanoids as amyloid β aggregation inhibitors in Alzheimer’s disease

ACS Fall 2021

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