Molecular mechanisms involved in the destabilization of two types of R3–R4 tau fibrils associated with chronic traumatic encephalopathy by Fisetin

Abstract

Chronic traumatic encephalopathy is a neurodegenerative tauopathy pathologically characterized by fibrillary tau aggregates in the depth of sulci. Clearing fibrous tau aggregates is considered a promising strategy in the treatment of CTE. Fisetin (FS), a natural polyphenolic small molecule, was confirmed to disassociate the tau filaments in vitro. However, the molecular mechanisms of FS in destabilizing the CTE-related R3–R4 tau fibrils remain largely unknown. In this study, we compared the atomic-level structural differences of the two types of CTE-related R3–R4 tau fibrils and explored the influence and molecular mechanisms of FS on the two types of fibrils by conducting multiple molecular dynamics (MD) simulations. The results reveal that the type 1 fibril displays higher structural stability than the type 2 fibril, with a lower root-mean-square-fluctuation value and higher β-sheet structure probability. FS can destabilize both types of fibrils by decreasing the β-sheet structure content, interrupting the mainchain H-bond network, and increasing the solvent accessible surface area and β7–β8 angle of the fibrils. H-bonding, π–π stacking and cation–π are the common interactions driving FS molecules binding on the two types of fibrils, while the hydrophobic interaction occurs only in the type 2 fibril. Due to the relatively short simulation time, our study captures the early molecular mechanisms. However, it does provide beneficial information for the design of drugs to prevent or treat CTE.