Misfolding and aggregation of microtubule-associated tau protein is implicated in a variety of neurodegenerative disorders (named tauopathies), including Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). AD is the most common type of dementia associated with aging, and CTE is a special tauopathy that mostly affects contact sports athletes (such as those active in American football and boxing). Experimental studies have found that tau acetylated on residue K353 exhibited a declined aggregation propensity
however, the underlying molecular mechanism remains elusive. In this study, we performed replica exchange and conventional molecular dynamics simulations of acetylated and unacetylated tau protein models in an explicit solvent. Our results revealed that the acetylated R4 (the fourth microtubule-binding repeat domain) dimer showed less β structure and more disordered conformations than the unacetylated one. K353 acetylation weakened peptide-peptide interactions and interrupted the salt-bridge network, thus inhibiting R4 dimerization. Besides, K353 acetylation reduced the β-sheet structure probability and induced loosely packed conformations of R3-R4 (the third and fourth microtubule-binding repeat regions) protofibrils. The replacement of the charged group by acyl on K353 resulted in the loss of K353-D358 salt bridges, leading to the enlargement of the β6-β7 angle and the distance between the carboxyl-terminal and β-turn region, finally eliciting an opened "H" configuration. Our work provided a clear picture of the inhibitory mechanisms of K353 acetylation on tau at the microscopic level, which may be helpful in the development of new therapeutics against tauopathies from the perspective of post-translational modification (PTMs).