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.