Abstract
Phosphorylation, the most popular post-translational modification of tau protein, plays an important role in regulating tau physiological functions. However, aberrant phosphorylation attenuates the binding affinity of tau to a microtubule (MT), resulting in MT destabilization followed by accumulation of neurofibrillary tangles in the brain. There are in total 85 potential phosphorylation sites in a full-length tau protein, and about half of them are abnormal as they occur in tau of Alzheimer's disease (AD) brain only. In this work, we investigated the impact of abnormal Ser289, Ser293, and Ser289/Ser293 phosphorylation on tau R2-MT binding and the conformation of tau R2 using molecular dynamics simulation. We found that the phosphorylation significantly affected R2-MT interaction and reduced the binding affinity of tau R2 peptides to MTs. Free energy decomposition analysis suggested that the post-translational modified residues themselves made a significant contribution to destabilize tau repeat R2-MT binding. Therefore, the phosphorylation may attenuate the binding affinity of tau to MTs. Additionally, the phosphorylation also enhanced helix-coil transition of monomeric R2 peptides, which may result in the acceleration of tau aggregation. Since these phosphorylated sites have not been examined in previous experimental studies, our finding through all-atom molecular dynamics simulations and free energy analysis can inspire experimental scientists to investigate the impact of the phosphorylation on MT binding and aggregation of full-length tau and the pathological roles of the phosphorylation at those sites in AD development through in vitro/in vivo assays.