Molecular basis of cross-interactions between Aβ and Tau protofibrils probed by molecular simulations

Abstract

Amyloid β-protein (Aβ) and Tau, two common pathogenic proteins associated with Alzheimer's disease (AD), cross-interact, and thus co-assemble into hybrid aggregates. However, molecular mechanism of the cross-interactions remains unclear. To explore the issue, docking and molecular dynamics (MD) simulations were coupled to study the cross-interactions between Aβ pentamer and Tau pentamer. Four stable hybrid decamer conformations including double layer, single layer, block, and part-in were obtained by protein-protein docking software HADDOCK 2.2. Then, MD simulations were used to explore the molecular mechanism of cross-interactions between Aβ pentamer and Tau pentamer. The results of MD simulations showed that the part-in structure was the most stable among all the above four representative ones. The binding energy between Aβ and Tau was about −759.77 kJ·mol−1 in the part-in structure. Moreover, the part-in conformation would undergo conformational transition, which would improve its hydrophobicity and make the structure more compact. This work offers a structural understanding of cross-interactions between Aβ and Tau linked to AD.