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

Abstract

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 Zn(2+) affects the Aβ aggregation in detail. Thus, molecular dynamics simulation was implemented to elucidate the changes of structure and residual hydrophobicity upon Zn(2+) coordination. Our results show that Zn(2+) 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 Zn(2+)-Aβ40 and Zn(2+)-Aβ42 was much higher than that of each monomer, since Zn(2+) 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 Zn(2+) 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 Zn(2+) in aggregation, which could be useful for further development of new drugs to inhibit Zn(2+)-Aβ aggregation.

Different zinc(II) complex species and binding modes at Aβ N-terminus drive distinct long range cross-talks in the Aβ monomers

“…Moreover, the presence of the salt-bridges, which involve Lys28, Lys16 and Arg5, is in agreement with the regulation of the solvent free-energy reported by Shi et al [20]. The stabilizing interaction of Phe19-Leu34 correlated with Aβ toxicity [79,50] was also observed in the deepest free-energy minimum conformation.…”

“…Indeed, several lines of evidence suggest that Aβ can coordinate divalent metal ions with high affinity constant values [19]. Intriguingly, -turn propensities in Aβ monomers depends also on metal ion coordination [20,21].…”

Multifunctionality of Acidulated Serum Albumin on Inhibiting Zn2+-Mediated Amyloid β-Protein Fibrillogenesis and Cytotoxicity

“…Aβ 42 monomers aggregate into oligomers and fibrils ( Figure 6A), 24 while Zn 2+ can rapidly induce the formation of Zn 2+ −Aβ 42 aggregates with large neurotoxicity ( Figure 6B). 7 However, in the presence of A-HSA, it could sequester Zn 2+ from Zn 2+ − Aβ 42 aggregates ( Figure 5C) and disturb the pathway of Zn 2+ -mediated Aβ 42 aggregation due to its stronger affinity for Zn 2+ (Table 2, Figure 6C). This function of A-HSA definitely comes from the extra carboxyl groups on the modified protein surface.…”

Zinc binding promotes greater hydrophobicity inAlzheimer's Aβ42peptide than copper binding: Molecular dynamics and solvation thermodynamics studies

“…12,16,[32][33][34][35] However, conflicting results have been reported. Some studies have suggested that the helical formation decrease in Aβ42 36,37 upon Zn 2+ binding, while an opposite effect have been noticed in other studies. 38 Moreover, Huy et al 39 have recently found a lower beta sheet and helix content but a higher random coil in Aβ42-Cu 2+ .…”