Molecular Simulations of Human and Mouse Aβ_1–16 at Different pH Values: Structural Characteristics toward Understanding Cu²⁺‐Coordinated Amyloid Beta Spheres

<jats:title>Abstract</jats:title><jats:p>As the main sequence responsible for metal ion coordination in the amyloid beta (Aβ) peptide, Aβ<jats:sub>1–16</jats:sub> plays a key role in the understanding of the aggregation of Aβ induced by Cu<jats:sup>2+</jats:sup> ions. There is no consensus on the nature of the coordination sphere of the Cu<jats:sup>2+</jats:sup>–Aβ complex so far due to the amorphous conformation of the Aβ<jats:sub>1–16</jats:sub> peptide itself and the pH dependence of Cu<jats:sup>2+</jats:sup>–Aβ coordination. The simulation reported here reveals that human Aβ<jats:sub>1–16</jats:sub> monomer has a U‐shape morphology, which is preserved at any pH. This morphology accommodates Cu<jats:sup>2+</jats:sup> ions with several binding sites and is also the basis for establishing a center‐distance statistical method (CDSM). Based on this CDSM, specific histidine residues for a Cu<jats:sup>2+</jats:sup>‐coordinated sphere are identified and the corresponding accurate pH range is established, indicating that the CDSM can be used as a reference to predict the potential coordination sites of metal ions in other amorphous peptides. By contrast, mouse Aβ<jats:sub>1–16</jats:sub> monomer has a more open and random morphology than human Aβ<jats:sub>1–16</jats:sub> due to the differences of three sequence positions. These mutations not only reduce the number of binding sites required by a stable Cu<jats:sup>2+</jats:sup>‐binding sphere but also diminish the capacity to generate salt bridges compared to the human peptide. These observations offer insights into the roles of three residues that differ in the mouse Aβ<jats:sub>1–16</jats:sub> and perhaps into the reasons mice seldom develop Alzheimer's disease.</jats:p>