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

Area of Science:

• Neuroscience
• Molecular Biology
• Biophysics

Background:

• Pathogenic mutations in microtubule-associated protein tau (MAPT) are key drivers of tauopathies.
• The V337M mutation within the PHF6** motif accelerates tau assembly, but its mechanism remains elusive.

Purpose of the Study:

• To elucidate the molecular mechanism by which the V337M mutation influences the conformational ensemble and aggregation behavior of PHF6** peptides.

Main Methods:

• Multiscale molecular dynamics simulations, including replica-exchange, conventional, and coarse-grained approaches.
• Analysis of conformational changes, beta-structure content, and interpeptide interactions.

Main Results:

• V337M mutation enhances beta-sheet structure and promotes compact oligomer formation.
• The mutation strengthens hydrogen bonds, salt-bridges, and residue-residue associations.
• V337M stabilizes persistent oligomerization and interconnected beta-sheet assemblies.

Conclusions:

• Beta-structure formation is essential for PHF6** oligomerization.
• The V337M mutation stabilizes interpeptide associations, leading to accelerated and more extensive oligomer formation.
• Mechanistic insights into mutation-driven tau oligomerization may advance understanding of tauopathy pathogenesis.