Acetylation and phosphorylation processes modulate Tau’s binding to microtubules: A molecular dynamics study

The microtubule-associated protein Tau has its normal function impaired when undergoing post-translational modifications. In this work, molecular modelling techniques were used to infer the effects of acetylation and phosphorylation in Tau's overall conformation, electrostatics, and interactions, but mostly in Tau's ability to bind microtubules. Reported harmful Lys sites were mutated by its acetylated form, generating eight different acetylated Tau (aTau) analogues. Similarly, phosphorylation sites found in normal brains and in Alzheimer’s lesioned brains were considered to design phosphorylated Tau (pTau) analogues. All these designed variants were evaluated in intracellular fluid and near a microtubule (MT) model. Our in silico findings demonstrated that the electrostatic changes, due to the absence of positive Lys’ charges in acetylation cases, or the increasingly negative charge in the phosphorylated forms, hamper the association to the MT tubulins in most cases. Post-translational modifications also pose very distinct conformations to the ones described for native Tau, which hinders the microtubule-binding region (MTBR) and turns difficult the expected binding. Our study elucidates important molecular processes behind Tau abnormal function which can inspire novel therapeutics to address Alzheimer’s disease. [Display omitted] •Post-translational modifications of Tau and their role in impairing Tau-microtubule binding were addressed.•Reported harmful acetylation and phosphorylation sites were modelled through molecular dynamics simulations.•Tau variants remain very mobile and explore a large conformational space, with only a few patches of secondary structure.•Acetylation and phosphorylation change the Tau’s electrostatic profile to less positive and more negative, respectively.•Electrostatics changes negatively impact Tau’s binding towards microtubules, more than the structural changes.