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. Replicaexchange molecular dynamics simulations demonstrate that the V337M mutation enhances β-structure and shifts PHF6** oligomers toward more compact aggregates.Interaction analyses show that the V337M mutation facilitates the formation of hydrogen bond and salt-bridge and strengthens the residue-resiude association, with the most pronounced enhancements involving residue 337 and its neighboring residues.Conventional molecular dynamics simulations reveal that 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 mutationlinked tauopathies.