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

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-1in 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.

Atomistic characterization of binding modes and affinity of peptide inhibitors to amyloid-β protein

Abstract The aggregation of amyloid β-protein （Aβ） is tightly linked to the pathogenesis of Alzheimer＇s disease. Previous studies have found that three peptide inhibitors （i.e., KLVFF, VVIA, and LPFFD） can inhibit Aβ aggregation and alleviate Aβ-induced neurotoxicity. How- ever, atomic details of binding modes and binding affinities between these peptide inhibitors and Aβ have not been revealed. Here, using molecular dynamics simulations and molecular mechanics Poisson Boltzmann surface area （MM/PBSA） analysis, we examined the effect of three peptide inhibitors （KLVFF, VVIA, and LPFFD） on their sequence-specific interactions with Aβ and the molecular basis of their inhibition. All inhibitors exhibit varied binding affinity to Aβ, in which KLVFF has the highest binding affinity, whereas LPFFD has the least. MM/PBSA analysis further revealed that different peptide inhibitors have different modes of interaction with Aβ, consequently hotspot binding residues, and underlying driving forces. Specific residue-based interactions between inhibitors and Aβ were determined and compared for illustrating different binding and inhibition mechanisms. This work provides structure-based binding information for further modifica- tion and optimization of these three peptide inhibitors to enhance their binding and inhibitory abilities against Aβ aggregation.