[Journal Club] X-ray absorption based approach to trap and accumulate a low populated and transient reaction intermediate of the Cu(II) reduction to Cu(I) in the peptide amyloid-β1-16

“Chasing the Elusive “In-Between” State of the Copper-Amyloidβ Complex by X-ray Absorption through Partial Thermal Relaxation after Photoreduction”, published by the group of Peter Faller in Angew Chem Int Ed Engl . 2023 Mar 3;e202217791. doi: 10.1002/anie.202217791

The main redox states of Cu are Cu(I) and Cu(II). A quite particularity of these two redox states is that their coordination chemistry is very different. Cu(II) is soft prefers diagonal, trigonal or tetrahedral coordination, whereas Cu(II) is borderline and square planar with or without axial ligands. This means with flexible ligands the coordination sphere is very different between Cu(I) and Cu(II).

Although this is a feature important in different field, a lot of research activity occurred on the cases of Cu-bound to intrinsically disordered proteins or peptides. The probably best known case is the complex of Cu to the peptide called amyloid-beta. The Cu-amyloid-beta is found in plaques of Alzheimer’s disease (AD) patients. In vitro, Cu-amyloid-beta is quite competent in catalysing the production of reactive radical species (ROS) and it was suggested that this contribute to the oxidative stress observed in AD.

To produce ROS by Cu-amyloid-beta, Cu has to cycle between Cu(I) and Cu(II). Hence, a very sluggish reaction is expected due to the very different coordination sphere (diagonal for Cu(I) and square planar for Cu(II)). To solve this discrepancy, indirect experimental studies and theoretical calculations of a number of groups in the last years, suggested a low populated state (< 1%) , that has an in-between coordination sphere is responsible for the efficient ROS production.

Here, we report a new experimental approach in this context, that allowed us for the first time to directly characterize the Cu coordination sphere of a state between the diagonal Cu(I) and square planar Cu(II). Hence, this gives experimental evidence for a state so far never spectroscopically investigated and supposed to be the state responsible for ROS production.