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

Abstract

As the main sequence responsible for metal ion coordination in the amyloid beta (Aβ) peptide, Aβ1-16 plays a key role in the understanding of the aggregation of Aβ induced by Cu(2+) ions. There is no consensus on the nature of the coordination sphere of the Cu(2+) -Aβ complex so far due to the amorphous conformation of the Aβ1-16 peptide itself and the pH dependence of Cu(2+) -Aβ coordination. The simulation reported here reveals that human Aβ1-16 monomer has a U-shape morphology, which is preserved at any pH. This morphology accommodates Cu(2+) 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(2+) -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 Aβ1-16 monomer has a more open and random morphology than human Aβ1-16 due to the differences of three sequence positions. These mutations not only reduce the number of binding sites required by a stable Cu(2+) -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 Aβ1-16 and perhaps into the reasons mice seldom develop Alzheimer's disease.

New Insights into the Structural and Binding Properties on Aβ Mature Fibrils Due to Histidine Protonation Behaviors

“…There are many factors, ,− such as β-/γ-secretase activity, metal ions, APP mutations, and pH environment, that can affect the Aβ conformational features during the aggregation process from Aβ monomers to Aβ oligomers/mature fibrils. Significantly, metal ions are very important factors in promoting the formation of Aβ aggregates and amyloid plaques. − Meanwhile, pH is also one of the factors to control Aβ aggregate and plaque formations.…”

Tautomeric Effect of Histidine on β-Sheet Formation of Amyloid Beta 1–40: 2D-IR Simulations

“…Even small perturbations of the physiological environment can in-fluence the chemical and dynamic properties of peptides and destroy the balance of production and clearance of Ab. Many studies have focused on the influence of external factors (3)(4)(5)(6) such as pH changes, amyloid precursor protein mutation, and the presence of metal ions on the aggregation of Ab. In particular, slightly acidic conditions can promote formation of b-sheets and aggregation of Ab, which may be one reason why the brains of AD patients are relatively acidic compared with the brains of normal people (7).…”

Tautomeric Effect of Histidine on the Monomeric Structure of Amyloid β-Peptide(1–40)

“…It is pathologically characterized by progressive intracerebral accumulation of amyloid β-peptides (Aβ) and tau protein. , The major component of plaques, Aβ fragments, is derived from the amyloid precursor protein (APP) by β- and γ-secretase proteolysis. , Approximately 90% of the Aβ fragments generated are the 40 residue fragment (Aβ(1–40)). , Aggregation of the fragments, including toxic oligomers, plays a crucial role in the pathogenesis of AD. − During Aβ aggregation, the “nucleated growth mechanism” has been accepted to describe the process of development from unfolded monomers to mature fibrils. That is, soluble and natively unfolded monomers first form β-structures, then generate the initial nucleus and proto-fibrils, and finally become mature fibrils. , Many factors, − such as pH environment, APP mutation, β-/γ-secretase’s activity, and metal ions, can destroy the frail balance between Aβ production and clearance − and induce aggregation.…”