Atomic Level Investigations of Early Aggregation of Tau43 in Water II. Tau43‐Aβ42 vs. Tau43‐Tau43 Dimerizations

Abstract

Amyloid β (Aβ) senile plaques and Tau neurofibrillary tangles (NFTs) are major hallmarks of Alzheimer's disease (AD). However, early stages of Tau aggregation are still limitedly recognized. Here, we present atomistic molecular dynamics simulations and thermodynamics characterizations of heterogeneous Tau43‐Aβ42 and homogeneous Tau43‐Tau43 dimerization processes. Two‐stage approaching‐accommodation mechanism after individual diffusive regime is observed. The approach step involves opposing forces driving two distant monomers to come closer to each other, which are the decrease in protein internal and water‐induced energies, respectively. In the accommodation step, a decrease in protein internal energy is the main driving force for stable compact structure formation. While the charged residues differently initiate and stabilize the dimer structures, the hydrophobic residues (11VQIVYK16 in Tau43 and 39VVIA42 in Aβ42) facilitate the formation of compact dimers, in agreement with experiments. Our results of Tau43‐Aβ42 and Tau43‐Tau43 dimerization will illuminate early onset mechanisms of AD pathology and corresponding therapeutic initiatives.