Dioxygen activation in the Cu–amyloid β complex

Abstract

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.

Free Superoxide is an Intermediate in the Production of H2O2 by Copper(I)‐Aβ Peptide and O2

“…[21,22] In contrast to the well supported production of H 2 O 2 and HOC,d etection of O 2 C À by nitro blue tetrazolium (NBT) or hydroethidine failed. [9,14,18,23,24] This seems coherent, because considering the redox potentials at neutral pH the electron reduction from O 2 to H 2 O 2 is ad own-hill reaction (exergonic), in contrast to the endergonic one-electron reduction of O 2 to O 2 C À .C omputational chemistry supported that Cu I -Ab can activate O 2 to form O 2 C À , [25,26] and that no O 2 C À is released during the H 2 O 2 production (O 2 C À was proposed as an intermediate bound to Cu-Ab). [9,14,18,23,24] This seems coherent, because considering the redox potentials at neutral pH the electron reduction from O 2 to H 2 O 2 is ad own-hill reaction (exergonic), in contrast to the endergonic one-electron reduction of O 2 to O 2 C À .C omputational chemistry supported that Cu I -Ab can activate O 2 to form O 2 C À , [25,26] and that no O 2 C À is released during the H 2 O 2 production (O 2 C À was proposed as an intermediate bound to Cu-Ab).…”

Towards High‐Throughput Modelling of Copper Reactivity Induced by Structural Disorder in Amyloid Peptides

“…The distances between Cu and N/O of Asp1 decrease with oxidation of Cu by dioxygen. The chance for interactions between Cu and the Asp1 carboxylate group has been addressed as an important contribution to the electron transfer to dioxy-gen. [2,7] Also, the greater chance for Od(Asp1) to enter Cu coordination when different Ab peptides are bridged by Cu has been observed in previouss tructural models. when superoxide is replaced by water,w hich is bound to the Cu centre axially,a si nt he stable square-pyramidal Cu II coordination environment.…”

“…Then, the distances are maintained Figure 1a nd Equations (2)-(4) for the meaning of the quantities. [7] Thus, the effect of carboxylate on the oxidised state of Cu II -Ab cannot be fully exerted, and the DE 2 values for thesea re positive in five of eight cases in whichO d(Asp1) approaches the Cu centre. The slight displacement of equatorial ligands,t ogether with the light push-and-pull movement of the axial water molecule, represents as mall reorganisationo ft he Cu site that hosts both oxidation states and the dioxygen electron shuttle.…”

“…We used the Gaussian 09 [42] code for the single-point calculation of energy for the final atomic configurations obtained in the previous DFT relaxation stage. [7],i ncludes al ocalised basis set of type 6-31 + G(d) for N, O, Ca nd H atoms, and LANL2DZ for Cu, the atomic core of which is described by ap seudopotential. [7],i ncludes al ocalised basis set of type 6-31 + G(d) for N, O, Ca nd H atoms, and LANL2DZ for Cu, the atomic core of which is described by ap seudopotential.…”

“…Cu coordination to Ab has been proposed to prevailu nder physiological conditions on the basis of EPR and NMR data for the oxidised form Cu II -Ab. [7,16] The activation of dioxygen by the Cu-Ab complex has been studiedi nv itro, by comparing the Cu-Ab 42 complex with a series of reference Cu-ligand (L) complexes and the free Cu aqua ion. [14] In the Cu II complex identified as Ia,C u 2 + is bound in as quare-planar geometry to Na nd O of Asp1, Nd1of His 6a nd an imidazole Na tom of His13 or His14,e ither of the same peptide or of another peptide in a multimeric state.…”