Towards a high-throughput modelling of copper reactivity induced by structural disorder in amyloid peptides

Transition metal ions often interact with disordered proteins. The affinity is high enough to compete with structured proteins, but the catalytic activity of the metal center is often out of control and, therefore, potentially dangerous for cells. An example is a single copper ion interacting with the amyloid-beta (Abeta) peptide and triplet dioxygen, an interaction that is fundamental in producing reactive oxygen species in neurodegeneration. In this work, we apply a high-throughput modelling of the Cu-Abeta-O2 system, with the aim at providing a tool to dissect the structural features that characterize dangerous Cu-based catalysts in neurodegeneration. The study shows that the production of superoxide is a process with low-energy intermediate species, once a small population of high-energy Cu(I)-Abeta complex is formed. This population is enhanced when Cu bridges two different peptides in 1:1 Cu:Abeta dimers. Despite the bias for high-energy reduced reactant species, the reduction of Cu(II)-Abeta product by superoxide can also occur, in addition to that by ascorbate, because the structural disorder produces a small population of oxidant species characterized by unstable Cu(II) coordination, coexisting with the most abundant reductant species, characterized by Cu(II) stable coordination.