Oxidative stress induced by redox-active metal cations such as Cu(2+) is a key event in the development of Alzheimer's disease. A detailed knowledge of the structure of Cu(2+)-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 Cu(2+)-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 CObackbone 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.

We investigate, by means of density-functional theory, the binding of dioxygen to Cu(I)-amyloid β (Aβ), one of the first steps in the oxidation of ascorbate by dioxygen. Cu, Aβ, ascorbate and dioxygen are all present in the synapse during neurodegeneration, when the above species can trigger an irreversible oxidative stress inducing the eventual death of neurons. The binding of dioxygen to Cu(I) is possible and its role in dioxygen activation of Cu ligands and of residues in the first coordination sphere is described in atomic detail. Dioxygen is activated when a micro-environment suitable for a square-planar Cu(2+) coordination is present and a negatively charged group like Asp 1 carboxylate takes part in the Cu coordination anti to O2.

The binding and electrochemical properties of the complexes Cu -HAH, Cu -HWH, Cu -Ac-HWH, Cu -HHW, and Cu -WHH have been studied by using NMR and UV/Vis spectroscopies, CV, and density functional calculations. The results obtained highlight the importance of the peptidic sequence on the coordination properties and, consequently, on the redox properties of their Cu complexes. For Cu -HAH and Cu -HWH, no cathodic processes are observed up to -1.2 V; that is, the complexes exhibit very high stability towards copper reduction. This behaviour is associated with the formation of very stable square-planar (5,5,6)-membered chelate rings (ATCUN motif), which enclose two deprotonated amides. In contrast, for non-ATCUN Cu -Ac-HWH, Cu -HHW complexes, simulations seem to indicate that only one deprotonated amide is enclosed in the coordination sphere. In these cases, the main electrochemical feature is a reductive irreversible one electron-transfer process from Cu to Cu , accompanied with structural changes of the metal coordination sphere and reprotonation of the amide. Finally, for Cu -WHH, two major species have been detected: one at low pH (<5), with no deprotonated amides, and another one at high pH (>10) with an ATCUN motif, both species coexisting at intermediate pH. The present study shows that the use of CV, using glassy carbon as a working electrode, is an ideal and rapid tool for the determination of the redox properties of Cu metallopeptides.

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Of the numerous ways in which two adenine and two guanines (N9 positions blocked in each) can be crosslinked by three linear metal moieties such as trans-a 2 Pt II (with a = NH 3 or MeNH 2 ) to produce open metalated purine quartets with exclusive metal coordination through N1 and N7 sites, one linkage isomer was studied in detail. The isomer trans,trans,trans-[{Pt(NH 3 ) 2 (N7-9-EtA-N1) 2 }{Pt-(MeNH 2 ) 2 (N7-9-MeGH)} 2 ][(ClO 4 ) 6 ]·3H 2 O (1) (with 9-EtA = 9-ethyladenine and 9-MeGH = 9-methylguanine) was crystallized from water and found to adopt a flat Z-shape in the solid state as far as the trinuclear cation is concerned. In the presence of excess 9-MeGH, a meander-like construct, (2) is formed, in which the two extra 9-MeGH nucleobases are hydrogen bonded to the two terminal platinated guanine ligands of 1. Compound 1, and likewise the analogous complex 1 a (with NH 3 ligands only), undergo loss of an ammonia ligand and formation of NH 4 + when dissolved in [D 6 ]DMSO. From the analogy between the behavior of 1 and 1 a it is concluded that a NH 3 ligand from the central Pt atom is lost. Addition of 1-methylcytosine (1-MeC) to such a DMSO solution reveals coordination of 1-MeC to the central Pt. In an analogous manner, 9-MeGH can coordinate to the central Pt in [D 6 ]DMSO. It is proposed that the proton responsible for formation of NH 4 + is from one of the exocyclic amino groups of the two adenine bases, and furthermore, that this process is accompanied by a conformational change of the cation from Z-form to U-form. DFT calculations confirm the proposed mechanism and shed light on possible pathways of this process. Calculations show that rotational isomerism is not kinetically hindered and that it would preferably occur previous to the displacement of NH 3 by DMSO. This displacement is the most energetically costly step, but it is compensated by the proton transfer to NH 3 and formation of U(ÀH + ) species, which exhibits an intramolecular hydrogen bond between the deprotonated N6H À of one adenine and the N6H 2 group of the other adenine. Finally the question is examined, how metal cross-linking patterns in closed metallacyclic quartets containing two adenine and two guanine nucleobases influence the overall shape (square, rectangle, trapezoid) and the planarity of a metalated purine quartet.