Molecular Dynamics Reveal Acetylation-Induced Tau Aggregation

Neurodegenerative diseases are one of the leading financial and medical burdens on the United States healthcare system. Without any gold-standard therapy, a projected 13 million individuals by 2050 will be left vulnerable. In this study, we seek to add to the literature on the role of post-translational modifications of tau in forming aggregates, which are the precursor to neurofibrillary tangles — a hallmark of neurodegenerative disease. Specifically, we aimed to study the role of acetylation at K311, a lysine residue on one of the hexapeptide motifs found to nucleate tau dimerization. In the present study, we performed a 250-ns molecular dynamics simulation of four peptides of the third-repeat of the microtubule-binding domain in a wildtype state and a modified state with the acetylated K311. We find that acetylation of the peptide results in a reduction of the conformational diversity of the system throughout the trajectory as well as a broader thermodynamic basin within the free energy landscape. We further find that the acetylated system assumes a more compact oligomeric complex and is engaged in more hydrogen bonding and intermolecular interactions with other peptides. Our final finding concludes that acetylation causes a shift of β-strand structure into ɑ-helical structure, consistent with the dimerizing ability of PHF6 — the hexapeptide motif that contains the acetylated tau. Molecular dynamics approaches serve as an ideal “first step” for bench scientists seeking to prioritize their research efforts in developing an inhibitory drug for the self-aggregation propensity of disease-state tau.