Dissecting the atomic effects of S305 phosphorylation on the aggregation of the core tau peptides of the first intermediate filament.

Tauopathies, containing aging-related Alzheimer's disease (AD) and contact sports-related chronic traumatic encephalopathy (CTE), etc., are neuropathologically characteristic of the tau protein aggregates in the brain. Targeting the oligomeric species formed in the route of tau fibrilization has been considered a promising therapeutic approach to prevent or treat tauopathies. In vitro experiment reported that S305 phosphorylation (Pho-S305) exerted a protective role in tau aggregation. However, the atomic effect and molecular mechanisms of Pho-S305 on tau aggregation are largely elusive. In this study, we performed replica exchange molecular dynamics (REMD) and classical molecular dynamics (MD) simulations, with a total simulation time of 57 μs, on tau peptides without and with Pho-S305. The protein model was a novel tau fragment (G302-S316), constituting the ordered core of a first intermediate amyloid (FIA) filament of AD- and CTE-specific tau filament. The REMD results revealed that Pho-S305 suppressed the β-sheet formation and weakened the peptide-peptide interaction, thus inhibiting the aggregation of the peptides. Additional MD simulations indicated that the oligomerization dynamics of the peptides were disturbed by Pho-S305. Our findings excavate the mechanistic information underlying the phosphorylation-induced inhibitive effects on tau302-316 aggregation, which may provide potential useful clues for the development of therapeutic avenues for tauopathies.