Molecular Simulations Reveal Distinct Energetic and Kinetic Binding Properties of [F]PI-2620 on Tau Filaments from 3R/4R and 4R Tauopathies.

Tauopathies are a class of neurodegenerative disorders characterized by the accumulation of tau protein filaments in the brain. On the basis of isoforms with three or four microtubule-binding repeats (3R or 4R) that constitute tau filaments, tauopathies can be divided into 3R, 4R, and 3R/4R tauopathies. [F]PI-2620 is a tau-positron emission tomography (PET) tracer that detects tau filaments in the 3R/4R tauopathy Alzheimer's disease (AD) and the 4R tauopathies corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) with differential binding characteristics. A multiscale simulation workflow, including molecular docking, molecular dynamics simulation, metadynamics, and Brownian dynamics, was applied to uncover the molecular basis for the different binding properties of [F]PI-2620 in these tauopathies. The energetically best binding sites of [F]PI-2620 in the AD-tau filament are located in the C-shaped groove of the filament core structure that is accessible to the outside. The most favorable binding sites in CBD-tau and PSP-tau filaments are localized to cavities in the inner filament core. Sites on the outer surface have higher binding free energies, and interaction of [F]PI-2620 at these sites was short-lived in the molecular dynamics simulations. Computationally predicted associated rates of [F]PI-2620 with the groove sites in the AD-tau filament were higher than association rates with the cavity sites in the CBD- and PSP-tau filaments. The results indicate that tau filaments in AD combine favorable energetic and kinetic properties with regard to tracer binding, while the binding of [F]PI-2620 to filaments in CBD and PSP is kinetically restricted. Our findings reveal that distinct structural, energetic, and kinetic properties of tau filaments from AD, CBD, and PSP govern their interaction with PET tracers, which highlights the possibility to achieve tau isoform specificity in future tracer developments.