Identification of a Novel Multifunctional Ligand for Simultaneous Inhibition of Amyloid-Beta (Aβ₄₂) and Chelation of Zinc Metal Ion

Abstract

Zinc binding to β-amyloid structure could promote amyloid-β aggregation, as well as reactive oxygen species (ROS) production, as suggested in many experimental and theoretical studies. Therefore, the introduction of multifunctional drugs capable of chelating zinc metal ion and inhibiting Aβ aggregation is a promising strategy in the development of AD treatment. The present study has evaluated the efficacy of a new bifunctional peptide drug using molecular docking and molecular dynamics (MD) simulations. This drug comprises two different domains, an inhibitor domain, obtained from the C-terminal hydrophobic region of Aβ, and a Zn2+ chelating domain, derived from rapeseed meal, merge with a linker. The multifunctionality of the ligand was evaluated using a comprehensive set of MD simulations spanning up to 3.2 μs including Aβ relaxation, ligand–Zn2+ bilateral interaction, and, more importantly, ligand–Zn2+–Aβ42 trilateral interactions. Analysis of the results strongly indicated that the bifunctional ligand can chelate zinc metal ion and avoid Aβ aggregation simultaneously. The present study illustrated that the proposed ligand has considerable hydrophobic interactions and hydrogen bonding with monomeric Aβ in the presence of zinc metal ion. Therefore, in light of these considerable interactions and contacts, the α-helical structure of Aβ has been enhanced, while the β-sheet formation is prevented and the α-helix native structure is protected. Furthermore, the analysis of interactions between Aβ and ligand–zinc complex revealed that the zinc metal ion is coordinated to Met13, the ending residue of the ligand and merely one residue in Aβ. The results have proven the previous experimental and theoretical findings in the literature about Aβ interactions with zinc metal ion and also Aβ interactions with the first domain of the proposed ligand. Moreover, the current research has evaluated the chelation using MD simulation and linear interaction energy (LIE) methods, and the result has been satisfactorily verified with previous experimental and theoretical (DFT) studies.

Evaluating the Multifunctionality of a New Modulator of Zinc-Induced Aβ Aggregation Using a Novel Computational Approach

“…It is noteworthy that the DFT data is very consistent with the results of the BAR method in the present study. Also, compared to the results of our previous work done by the linear interaction energy (LIE) method, which has some underestimating error, the free energy calculated in this study is more consistent with experimental investigations and DFT …”

“…Also, compared to the results of our previous work done by the linear interaction energy (LIE) method, which has some underestimating error, the free energy calculated in this study is more consistent with experimental investigations and DFT. 45 2.2. Peptide−Zn 2+ Interaction with Different Aβ Forms.…”

“…Shamloo et al have evaluated the ability of bifunctional peptides in MD simulations. However, they have concentrated solely on the study of chelation and ultimately the interaction of the peptide–ion complex with Aβ monomers. , However, it is essential that the multifunctional peptides proposed for the treatment of AD, simultaneously with chelating metal ions, interact effectively with Aβ accumulations.…”

Peptide-Based Materials That Exploit Metal Coordination

“…Co (II) [95,96], Pt (II) [97][98][99], Ru (II) [100,101], and heterometallic Pt(II)-Ru(II) [102] complexes proved effective too for this purpose, also through chelation of Cu (II) that was captured from Aβ [103]. It is thus not surprising that peptides binding Cu(II) [104][105][106][107][108][109][110], Zn(II) [111][112][113], and Cd(II) [112] have been successfully designed to inhibit Aβ fibrillation. Researchers have sought to combine gold NPs with Cu (II) chelating peptides to develop effective inhibitors (Figure 8) [114].…”

Semax, a Synthetic Regulatory Peptide, Affects Copper-Induced Abeta Aggregation and Amyloid Formation in Artificial Membrane Models

“…Although results are often contradictory, there is a general consensus that the Aβ/Cu 2+ complex formation drives and modulates the final end of the aggregation process. − It was demonstrated that, depending on the protein/ion ratio, the aggregation is driven toward amorphous or fibrillar structures. ,− In the last decade, many peptide inhibitors of Aβ aggregation have been proposed − and evaluated for the treatment of AD . Peptides capable of both preventing fibril formation and sequestering free Cu 2+ ion are particularly interesting. − …”