Pathogenic Mutation ΔK280 Promotes Hydrophobic Interactions Involving Microtubule‐Binding Domain and Enhances Liquid‐Liquid Phase Separation of Tau

Abstract Liquid‐liquid phase separation (LLPS) of tau protein can initiate its aggregation which is associated with Alzheimer's disease. The pathogenic mutation ΔK280 can enhance the aggregation of K18, a truncated tau variant comprising the microtubule‐binding domain. However, the impact of ΔK280 on K18 LLPS and underlying mechanisms are largely unexplored. Herein, the conformational ensemble and LLPS of ΔK280 K18 through multiscale molecular simulations and microscopy experiments are investigated. All‐atom molecular dynamic simulations reveal that ΔK280 significantly enhances the collapse degree and β‐sheet content of the K18 monomer, indicating that ΔK280 mutation may promote K18 LLPS, validated by coarse‐grained phase‐coexistence simulations and microscopy experiments. Importantly, ΔK280 mutation promotes β‐sheet formation of six motifs (especially PHF6), increases the hydrophobic solvent exposure of PHF6* and PHF6, and enhances hydrophobic, hydrogen bonding, and cation‐π interactions involving most of the motifs, thus facilitating the phase separation of K18. Notably, ΔK280 alters the interaction network among the six motifs, inducing the formation of K18 conformations with high β‐sheet contents and collapse degree. Coarse‐grained simulations on full‐length tau reveal that ΔK280 promotes tau LLPS by enhancing the hydrophobic interactions involving the microtubule‐binding domain. These findings offer detailed mechanistic insights into ΔK280‐induced tau pathogenesis, providing potential targets for therapeutic intervention.