Effect of site-specific lysine acetylation on tau binding to microtubules: mechanistic insights from all-atom...

Tau protein plays a critical role in stabilizing microtubules (MTs) within neuronal axons, while its function can be altered by aberrant post-translational modifications, contributing to tauopathies such as Alzheimer's disease and chronic traumatic encephalopathy. Experimental studies have found that acetylation at K274, K280, and K281 disrupts tau-MT binding. However, the underlying molecular mechanism remains elusive. Herein, we performed all-atom molecular dynamics simulations to systematically investigate how acetylation at these three sites within the second MT-binding repeat (R2) of tau affects the conformation of the Tau_R2-MT complex. We found that acetylation at K274, K280, and K281 weakens the overall stability of the Tau_R2-MT complex. MM/PBSA calculations corroborate a decrease in binding affinity between Tau_R2 and MT, with the K280-acetylated system showing the largest loss and electrostatics accounting for most of the change. Contact analysis revealed site-specific patterns, with K274 and K281 acetylation primarily affecting the interfacial contacts at the C-terminal region of Tau_R2, while K280 acetylation affected both the N- and C-terminal regions. Moreover, acetylation induced a more compact Tau_R2 conformation and enhanced intramolecular contacts, further compromising the stability of MT. This study provides site-specific mechanistic insights into how lysine acetylation weakens the Tau_R2-MT binding and can guide the development of new therapeutics against tauopathies from the perspective of post-translational modifications.