Computational Insights into the Destabilization of Baicalein on the Tau Protofibrils Associated with Alzheimer’ s Disease and Chronic Traumatic Encephalopathy

Tauopathies are a subgroup of neurodegenerative diseases pathologically typified as tau protein aggregate deposits in the brain, including Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). AD is the most common cause of dementia, and CTE is a unique tauopathy affecting contact sports athletes, such as those active in American football and boxing, among others. It is revealed that the three-dimensional configurations of the protofibrils in AD and CTE-specific tau filaments are rather similar. Baicalein (BA) is a natural polyphenol extracted from <i>Scutellaria baicalensis</i> Georgia and was confirmed to disaggregate the preformed tau fibrils <i>in vitro</i>. However, the atomic effects and underlying mechanisms of BA on the AD- and CTE-specific tau protofibrils are largely unknown. In this study, we conducted all-atom molecular dynamics (MD) simulations on the two types of protofibrils without and with BA. The results revealed that BA could decrease the structural stability and reduce the β-sheet structure probability of the two types of protofibrils. BA extended the three-dimensional conformations of the AD-type protofibril in the vertical axis direction while it extended the CTE-type protofibril in the horizontal axis direction. BA preferentially bound with the β-sheet fragments of the two types of protofibrils through hydrophobic, H-bonding, and π-π stacking interactions, while the binding sites showed many differences. In addition, the cation-π interaction only existed between BA and the AD-type protofibril. Our work provides useful theoretical implications for the design of drugs to prevent or delay the development of AD and CTE.