Disclosing the Template-Induced Misfolding Mechanism of Tau Protein by Studying the Dissociation of the Boundary Chain from the Formed Tau Fibril Based on a Steered Molecular Dynamics Simulation

The level of tau aggregation into neurofibrillary tangles, including paired helical filament (PHF) and straight filament (SF), is closely associated with Alzheimer's disease. Despite the pathological importance of misfolding and aggregation of tau, the corresponding mechanism remains unclear. Therefore, to uncover the misfolding mechanism of the tau monomer upon induction of formed PHF and SF, in this study, a conventional molecular dynamics simulation combined with a steered molecular dynamics simulation was performed to study the dissociation of the boundary chain. Interestingly, our results show that the dissociation mechanisms of the boundary chain in PHF and SF are different. In PHF, the boundary chain begins to dissociate from regions beta 2 and beta 3 and ends at beta 8. However, in SF, it is simultaneously dissociated from beta 1 and beta 8 and ends at beta 5. The dissociation of the boundary chain is the reverse of template-induced misfolding of the monomer. Therefore, we can deduce the misfolding mechanism of the monomer upon induction of the template. For PHF, beta 8 first interacts with the template by hydrophobic interaction. Then beta 7, beta 6, beta 5, beta 4, and beta 1 sequentially bind to the template by electrostatic and hydrophobic interactions. After beta 1 binds to the template, beta 2 and beta 3 very quickly bind to the template through hydrophobic interaction. For SF, beta 5 of the monomer first interacts with the template by electrostatic attraction. Then beta 4 and beta 6, beta 3 and beta 7, and beta 2 and beta 8 bind to the template in turn. Finally, beta 1 and beta 8 are fully bound to the template by hydrophobic interaction. The obtained results will be vital for understanding the earlier events during misfolding and aggregation of tau.