Molecular Simulations of Human and Mouse Aβ1–16 at Different pH Values: Structural Characteristics toward Understanding Cu2+‐Coordinated Amyloid Beta Spheres

As the main sequence responsible for metal ion coordination in the amyloid beta (Aβ) peptide, Aβ_1–16 plays a key role in the understanding of the aggregation of Aβ induced by Cu²⁺ ions. There is no consensus on the nature of the coordination sphere of the Cu²⁺–Aβ complex so far due to the amorphous conformation of the Aβ_1–16 peptide itself and the pH dependence of Cu²⁺–Aβ coordination. The simulation reported here reveals that human Aβ_1–16 monomer has a U‐shape morphology, which is preserved at any pH. This morphology accommodates Cu²⁺ 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 Cu²⁺‐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_1–16 monomer has a more open and random morphology than human Aβ_1–16 due to the differences of three sequence positions. These mutations not only reduce the number of binding sites required by a stable Cu²⁺‐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_1–16 and perhaps into the reasons mice seldom develop Alzheimer's disease.