Effects of Metal Ions on Aβ₄₂ Peptide Conformations from Molecular Simulation Studies

In this study, we investigate the conformational characteristics of full-length Aβ₄₂ peptide monomers in the presence of Na⁺ and Zn²⁺ metal ions using atomistic molecular dynamics (MD) simulations with an aim to explore the possible driving forces behind enhanced aggregation rates of the peptides in the presence of salts. The calculations reveal that the presence of metal ions shifts the conformational equilibrium more toward the compact ordered Aβ structures. Such compact ordered structures stabilized by distant nonlocal contacts between two crucial hydrophobic segments, hp1 and hp2, primarily through two important hydrophobic aromatic residues, Phe-19 and Phe-20, are expected to trigger the aggregation process at a faster rate by populating and stabilizing the aggregation prone structures. Formation of a significant number of such distant contacts in the presence of Na⁺ ions has also been found to result in breaking of the N-terminal helix. On the contrary, binding of Zn²⁺ ion to Aβ peptide is highly specific, which stabilizes the N-terminal helix instead of breaking it. This explains why the aggregation rate of Aβ peptides is higher in the presence of divalent Zn²⁺ ions than monovalent Na⁺ ions. Relatively higher overall stability of the most populated Aβ peptide monomers in the presence of Zn²⁺ ions has been found to be associated with specific Zn²⁺-Aβ binding and significant free energy gain.