Ab initio modelling of the structure and redox behaviour of copper(I) bound to a His–His model peptide: relevance to the β-amyloid peptide of Alzheimer’s disease

Abstract

A contributing factor to the pathology of Alzheimer's disease is the generation of reactive oxygen species, most probably a consequence of the beta-amyloid (Abeta) peptide coordinating copper ions. Experimental and theoretical results indicate that His13 and His14 are the two most firmly established ligands in the coordination sphere of Cu(II) bound to Abeta. Abeta1-42 is known to reduce Cu(II) to Cu(I). The Abeta-Cu(II) complex has been shown to catalytically generate H(2)O(2) from reducing agents and O(2). Cu(II) in the presence of Abeta has been reported to have a formal reduction potential of +0.72-0.77 V (vs. the standard hydrogen electrode). Quantum chemical calculations using the B3LYP hybrid density functional method with the 6-31G(d) basis set were performed to model the reduction of previously studied Cu(II) complexes representing the His13-His14 portion of Abeta (Raffa et al. in J. Biol. Inorg. Chem. 10:887-902, 2005). The effects of solvation were accommodated using the CPCM method. The most stable complex between Cu(I) and the model compound, 3-(5-imidazolyl)propionylhistamine (1) involves tricoordinated Cu(I) in a distorted-T geometry, with the Npi of both imidazoles as well as the oxygen of the backbone carbonyl bound to copper. This model would be the most likely representation of a Cu(I) binding site for a His-His peptide in aqueous solution. A variety of possible redox processes are discussed.

Designing a functional type 2 copper center that has nitrite reductase activity within α-helical coiled coils

“…Although the spectra at these two pH values are different, possibly because of a slight change of the geometry of the (His) 3 site, they prove the Cu(I) coordination to the imidazole nitrogens. The presence of multiple peaks in the spectra of Cu(I)(TRIL23H) 3 + is likely the result of the presence of different similar energy conformations at the Cu(I)(His) 3 site, an observation consistent with what was observed for the Cu(I) adduct of the 1-42 fragment of β-amyloid (25). Importantly, given the 1:1 Cu(I):(TRIL23H) 3 stochiometry of these experiments, the formation of two-stranded Cu(I)(TRIL23H) 2 + is ruled out by the absence of residual signals for the apo-peptide.…”

Modeling Cu2+-Aβ complexes from computational approaches

“…In particular, Rauk et al have used B3LYP [33][34][35] functional to evaluate the complex stabilities, ligand preferences and reaction pathways for a series of model systems of Cu +/2+ -Aβ complexes. [28][29][30][31]36 These model systems have been very useful to study different coordination spheres as well as to determine some molecular properties such as standard reduction potentials (SRP) or stability constants, the computed values being in reasonable agreement with experimental results. 27 Model systems have also been used to study the possible reaction pathways allowing the generation of H 2 O 2 catalyzed by Cu-Aβ complexes.…”

“…The first studies, mainly carried out by Rauk et al, [27][28][29][30][31][32] considered the first coordination sphere of the metal cation at a quantum mechanical level. Other studies have partially incorporated the effect of the rest of the peptide using truncated models such as Aβ (1-7) 37 or Cu-Aβ (1-16) complexes.…”

“…Limitations on the level of theory used can partially be overcome by adding the difference obtained between the calculated and experimental second ionization energy of atomic copper to the calculated ∆H. 31 Alternatively, an empirical correction, defined as the difference between the calculated and experimental SRP for the free metal ion in aqueous solution can be added to the values calculated for the Cu +/2+ -Aβ couple. 40,64 This latter approximation has been considered to evaluate the SRP of Cu 2+ -Aβ complexes involving different coordination spheres.…”

“…Early studies [27][28][29][30][31][32] used QM methods to compute model systems that include only the first coordination sphere of the metal. In particular, Rauk et al have used B3LYP [33][34][35] functional to evaluate the complex stabilities, ligand preferences and reaction pathways for a series of model systems of Cu +/2+ -Aβ complexes.…”