Zn²⁺ Effect on Structure and Residual Hydrophobicity of Amyloid β‑Peptide Monomers

The aggregation of amyloid β-peptide (Aβ peptide) has been associated with the pathogenesis of Alzheimer’s disease (AD). In the present study, we aimed to disclose how Zn²⁺ affects the Aβ aggregation in detail. Thus, molecular dynamics simulation was implemented to elucidate the changes of structure and residual hydrophobicity upon Zn²⁺ coordination. Our results show that Zn²⁺ can strongly influence the structural properties of Aβ40 and Aβ42 by reducing helical formation and increasing turn formation to expose the hydrophobic regions. Furthermore, hydrophobicity of Zn²⁺-Aβ40 and Zn²⁺-Aβ42 was much higher than that of each monomer, since Zn²⁺ binding can significantly influence the hydrophilic domains of Aβ. The further analyses indicate that not only four residues (H6, E11, H13, and H14) but also R5, D7, K16, K28, and terminal residues influence hydrophobicity upon Zn²⁺ coordination. Importantly, R5, K16, and K28 play a crucial role to regulate solvation-free energies. This work is helpful to understand the fundamental role of Zn²⁺ in aggregation, which could be useful for further development of new drugs to inhibit Zn²⁺-Aβ aggregation.