BPS2026 – Combining computational methods to probe the allosteric effects of tau on microtubules

Tau is a microtubule-associated protein (MAP) localized exclusively to neuronal cells. Its phosphorylation is implicated in a number of neurodegenerative diseases called tauopathies, of which Alzheimer’s disease is a notable example. While healthy tau helps microtubules avoid catastrophe and achieve greater lengths, the underlying mechanism is unclear. Tau’s microtubule binding region (MTBR) contains 4 pseudorepeats. Flanking the MTBR are additional regions that are necessary for tau to form dense condensates on the microtubule that block motor proteins (e.g., kinesin-1), inhibit severing proteins, and compact the lattice longitudinally. These effects are longer range than those of other neuronal MAPs. We used MD simulations along with normal mode analysis to investigate these functions of tau, and employed explainable AI (xAI) methods to determine the regions of the tubulin monomer allosterically affected by tau. The first two MTBR repeats (R1 and R2) were simulated separately. The isotype of β tubulin was also varied between β3, the predominant isotype in the brain, and Beta1, an isotype also present in the brain but more commonly found in blood cells. Our results demonstrate that both repeats have tuned their effects to be stronger and more targeted to particular regions on β3. The repeats increase the overall flexibility of the tubulin, which may explain how tau is able to let microtubules grow longer without fully stabilizing them. Both repeats show a capability to inhibit kinesin-1 and severing proteins, but they each inhibit them differentially. xAI methods also reveal that the intradimer interface distinguishes between R1 and R2, while the interdimer interface is where compaction of the lattice occurs.