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Alzheimer’s disease is the most fatal neurodegenerative disorder. Many researches have found that the process of amyloid-β(Aβ) amyloidogenesis is the main cause. However, the molecular basis of aggregation of Aβand affinity between Aβand peptide inhibitor remains unclear. Here,Molecular dynamics simulations and molecular mechanics-Poisson-Boltzmann surface area method (MM/PBSA) were performed to investigate the molecular mechanism of aggregation of Aβand the affinity between Aβand phage-display selected affibody protein ZAβ.In the Aβ17-42 pentamer, a per-residue decomposition of the binding free energy and pair interaction analysis have been performed to identify the hot spots contributing most to the binding process. The results indicate that the nonpolar interactions and hydrogen bonding interactions provide the main driving force for the binding process. Residues V18, F19, F20, E22, D23, V24, K28, L34, M35, V36, V39, V40 and I41 contribute obviously. Between two adjacent monomers, the nonpplar interactions are the first for two residues in the same site, while the main binding force between two residues in the adjacent site is the hydrogen bonding interactions. In addition, the salt bridge between D23 and K28 is also important for Aβaggregation.Furthermore, the same method was performed to investigate the molecular mechanism of stabilization of a beta-hairpin in Aβ16-40 by the affibody protein ZAβ. The results indicate that ZAβbinds the critical residues F19、F20、A21、E22、D23、K28、L34、V36、V40 of Aβ. ZAβstabilizes Aβ16-40 by nonpolar interactions and electrostatic interactions. Free energy decomposition results indicate that the residues ofβ-strand and coil, E15, I16, V17, Y18, L19, P20, N21, L22, are the hot spots of ZAβ. On the contrary, theα-helix of ZAβalmost doesn’t interact with Aβ. ZAβstabilizes theβ-sheet by burying both of the mostly nonpolar faces of the Aβhairpin within a large hydrophobic tunnel-like cavity formed byα-helix to block other Aβ. The identified binding motif can be used as the starting point for the rational design of high affinity peptide inhibitors for Aβaggregation. High affinity site and large accessory structure are necessary for the efficient peptide inhibitors. High affinity site can bind to the hot spots of Aβcompetitively, and large accessory structure blocks another Aβmononers.
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