Multiscale simulations reveal the driving forces underlying V337M-induced tau core fragment aggregation

Abstract

Pathogenic microtubule-associated protein tau (MAPT) mutations play an important role in tauopathies by altering tau assembly and early aggregation. The V337M mutation, located within the aggregation-prone PHF6** motif of tau, is known to accelerate tau assembly, while its molecular mechanism is unclear. Here, we employ multiscale molecular dynamics simulations, combining replica-exchange, conventional and coarse-grained approaches, to elucidate how the V337M mutation reshapes the conformational ensemble and aggregation behavior of PHF6** peptides. Replica-exchange molecular dynamics simulations demonstrate that the V337M mutation enhances the β-structure and shifts PHF6** oligomers toward more compact aggregates. Interaction analyses show that the V337M mutation facilitates the formation of hydrogen bonds and salt-bridges and strengthens the residue–residue association, with the most pronounced enhancements involving residue 337 and its neighboring residues. Conventional molecular dynamics simulations reveal that the V337M mutation promotes persistent oligomerization and stabilizes β-sheet assemblies in larger PHF6** systems. Coarse-grained simulations establish that β-structure formation is a prerequisite for PHF6** oligomerization and the V337M mutation stabilizes interpeptide association, leading to earlier oligomer formation and more extensively interconnected oligomers. This study provides mechanistic insights into mutation-enhanced tau oligomerization, which may be helpful for an in-depth understanding of the pathogenesis of mutation-linked tauopathies.