Aberrant S293 Phosphorylation Drives Oligomerization of Tau Repeat R2: Insights from Molecular Dynamics Simulations

Aberrant phosphorylation, which is absent in healthy brains but present exclusively in the brains of individuals with Alzheimer's disease (AD), plays a critical role in AD development. It causes the dissociation of tau protein from microtubules, followed by the aggregation of tau protein into brain-toxic oligomers and fibrils. In our previous study, we investigated the impact of abnormal phosphorylation at S289 (pS289) on the oligomerization of tau repeat R2 peptides. In this work, we continue to investigate the effect of aberrant phosphorylation at residue S293 (pS293) on the R2 peptides. Our result indicated that pS293 also promotes oligomerization, which is similar to pS289. Both the phosphorylation-enhanced intramolecular and intermolecular interactions and β-sheet formation of phosphorylated R2 compared to that of the wild type. We observed that Na⁺ can bridge two pS293 residues to form pS293--Na⁺-pS293 triad in the R2 dimer, a phenomenon also observed for the pS289 R2 dimer. However, the impact of pS293 was different from that of pS289 in terms of the secondary structural profile of both monomeric and dimeric R2 peptides. Our findings suggest that phosphorylation at S293 should be taken into consideration in the inhibitor screening of tau oligomerization.