Molecular Mechanism in the Disruption of Chronic Traumatic Encephalopathy-Related R3–R4 Tau Protofibril by Quercetin and Gallic Acid: Similarities and Differences

Chronic traumatic encephalopathy (CTE) is a unique progressive neurodegenerative tauopathy pathologically related to the aggregation of the tau protein to neurofibrillary tangles. Disrupting tau oligomers (protofibril) is a promising strategy to prevent CTE. Quercetin (QE) and gallic acid (GA), two polyphenol small molecules abundant in natural crops, were proved to inhibit recombinant tau and the R3 fragment of human full-length tau in vitro. However, their disruptive effect on CTE-related protofibril and the underlying molecular mechanism remain elusive. Cryo-electron microscopy resolution reveals that the R3-R4 fragment of tau forms the core of the CTE-related tau protofibril. In this study, we conducted extensive all-atom molecular dynamics simulations on CTE-related R3-R4 tau protofibril with and without QE/GA molecules. The results disclose that both QE and GA can disrupt the global structure of the protofibril, while GA shows a relatively strong effect. The binding sites, exact binding patterns, and disruptive modes for the two molecules show similarities and differences. Strikingly, both QE and GA can insert into the hydrophobic cavity of the protofibril, indicating they have the potential to compete for the space in the cavity with aggregation cofactors unique to CTE-related protofibril and thus impede the further aggregation of the tau protein. Due to relatively short time scale, our study captures the early disruptive mechanism of CTE-related R3–R4 tau protofibril by QE/GA. However, our research does provide valuable knowledge for the design of supplements or drugs to prevent or delay the development of CTE.