3D Structures and Redox Potentials of Cu²⁺–Aβ(1–16) Complexes at Different pH: A Computational Study

Abstract

Oxidative stress induced by redox-active metal cations such as Cu²⁺ is a key event in the development of Alzheimer’s disease. A detailed knowledge of the structure of Cu²⁺–Aβ complex is thus important to get a better understanding of this critical process. In the present study, we use a computational approach that combines homology modeling with quantum-mechanics-based methods to determine plausible 3D structures of Cu²⁺–Aβ­(1–16) complexes that enclose the different metal coordination spheres proposed experimentally at different pH values. With these models in hand, we determine their standard reduction potential (SRP) with the aim of getting new insights into the relation between the structure of these complexes and their redox behavior. Results show that in all cases copper reduction induces CO_backbone decoordination, which, for distorted square planar structures in the oxidized state (Ia_δδ, IIa_εδε, IIa_εεε, and IIc_ε), leads to tricoordinated species. For the pentacoordinated structural candidate Ib_δε with Glu11 at the apical position, the reduction leads to a distorted tetrahedral structure. The present results highlight the importance of the nature of the ligands on the SRP. The computed values (with respect to the standard hydrogen electrode) for complexes enclosing negatively charged ligands in the coordination sphere (from −0.81 to −0.12 V) are significantly lower than those computed for models involving neutral ligands (from 0.19 to 0.28 V). Major geometry changes induced by reduction, on both the metal site and the peptide configuration, are discussed as well as their possible influence in the formation of reactive oxygen species