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

The high concentration of zinc metal ions in Aβ aggregations is one of the most cited hallmarks of Alzheimer's disease (AD), and several substantial pieces of evidence emphasize the key role of zinc metal ions in the pathogenesis of AD. In this study, while designing a multifunctional peptide for simultaneous targeting Aβ aggregation and chelating the zinc metal ion, a novel and comprehensive approach is introduced for evaluating the multifunctionality of a multifunctional drugs based on computational methods. The multifunctional peptide consists of inhibitor and chelator domains, which are included in the C-terminal hydrophobic region of Aβ, and the first four amino acids of human albumin. The ability of the multifunctional peptide in zinc ion chelation has been investigated using molecular dynamics (MD) simulations of the peptide-zinc interaction for 300 ns, and Bennett's acceptance ratio (BAR) method has been used to accurately calculate the chelation free energy. Data analysis demonstrates that the peptide chelating domain can be stably linked to the zinc ion. Besides, the introduced method used for evaluating chelation and calculating the free energy of peptide binding to zinc ions was successfully validated by comparison with previous experimental and theoretical published data. The results indicate that the multifunctional peptide, coordinating with the zinc metal ion, can be effective in Aβ inhibition by preserving the native helical structure of the Aβ₄₂ monomer as well as disrupting the β-sheet structure of Aβ₄₂ aggregates. Detailed assessments of the Aβ₄₂-peptide interactions elucidate that the inhibition of Aβ is achieved by considerable hydrophobic interactions and hydrogen bonding between the multifunctional peptide and the hydrophobic Aβ regions, along with interfering in stable bridges formed inside the Aβ aggregate.