Stability of transient Cu⁺Aβ (1–16) species and influence of coordination and peptide configuration on superoxide formation

Abstract

Accumulation of Cu²⁺ redox active metal cations has been associated with the oxidation damage observed in the development of Alzheimer disease. Copper ions can interact with accumulated amyloid-β (Aβ) peptides and mediate the toxicity of the peptide through the catalytic production of H₂O₂. The first step of this catalytic process is the reduction of Cu²⁺Aβ complex and the activation of O₂ by the reduced species. This work addresses the stability of the reduced complexes and superoxide formation by Cu⁺Aβ (1–16) complexes. We have considered the experimentally proposed coordination spheres for Cu²⁺Aβ (1–16) which includes the terminal amino group, two His and the CO from Asp1 (complex I), three histidines and the CO of Ala2 (complex IIa), and one His, the NH₂ terminus, the deprotonated amide nitrogen and carbonyl oxygen of Ala2 (complex IIc). Results from ab initio molecular dynamics calculations show that, after reduction of the square planar Cu²⁺Aβ complex, decoordination of the O atom occurs in the first steps and tricoordinated structures are stable during the simulation time scale, thereby being prone to O₂ activation. Quantum chemical calculations on small models and Cu⁺Aβ (1–16) interacting with O₂ indicate that the preference for O₂ activation follow the order IIc > IIa > I. In all these cases energy barriers for superoxide formation are less than 4 kcal mol⁻¹ and thus kinetically favorable. Comparison of small model systems and Cu⁺Aβ (1–16) have pointed out that peptide configuration may significantly influence the O₂ activation through second sphere interactions.