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

Abstract

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 centre is often out of control and, therefore, potentially dangerous for cells. An example is a single copper ion interacting with the amyloid-β (Aβ) peptide and triplet dioxygen, an interaction that is fundamental in producing reactive oxygen species in neurodegeneration. High-throughput modelling of the Cu-Aβ-O system was performed with the aim of providing a tool to dissect the structural features that characterise dangerous Cu-based catalysts in neurodegeneration. This study showed that the production of superoxide is a process with low-energy intermediate species, once a small population of high-energy Cu -Aβ complex is formed. This population is enhanced when Cu bridges two different peptides in 1:1 Cu:Aβ dimers. Despite the bias for high-energy reduced reactant species, the reduction of Cu -Aβ product by superoxide can also occur, in addition to that by ascorbate, because the structural disorder produces a small population of oxidant species characterised by unstable Cu coordination, coexisting with the most abundant reductant species, characterised by stable Cu coordination.

Computational Model to Unravel the Function of Amyloid-β Peptides in Contact with a Phospholipid Membrane

“…70 The Cu 2+ coordination geometry in this empirical force-field is approximately square-planar, with the fifth axial coordination always available to electrostatic interactions, as shown in previous simulations performed with the same force-field. 36 The root-mean-square deviation (rmsd) between configurations obtained with this empirical force-field and minimal-energy configurations obtained including explicit electrons (like in density-functional theory applied to truncated models) is small.…”

“…Divalent cations change membrane structure, transport properties, 29−31 and reactivity, 32 thus possibly promoting protein aggregates resembling ion channels and membrane pores. dioxygen molecules, 35,36 and promoting oxidative pathways. 37−40 Because of these important issues, the modeling of interactions of divalent cations with lipid charged and zwitterionic membranes is becoming a challenge.…”

“…45,46 Therefore, we separately applied two modeling techniques: (i) a naive nonbonded model of Mg 2+ that has been used to model the free energy change for the exchange reaction between the water solution and a protein, 47 and for neutralizing RNA phosphate groups; 48 (ii) a bonded model of Cu 2+ that has been applied to describe a well-documented binding site for Cu− Aβ (1−42) observed in experiments 49−51 and extensively modeled by MD simulations. 36,52 The models describe interactions between, respectively, Mg 2+ aqua-ions, Aβ (1−42), and Cu(II)−Aβ(1−42) monomers with DMPC bilayers, the latter being a well-studied molecular model of the biological membrane. The simple model used for the Mg divalent aqua-ion 47,48 can depict a first approximation of the effects of Cu 2+ ions that have the size similar to Mg 2+ when not bound to proteins.…”

“…While physiological Cu­(II) concentration released within the synaptic cleft during synaptic vesicle release is 15 μM, it achieves 300 μM concentration upon neuronal depolarization. , The hypothesis of copper buffering activity of membrane proteins was proposed for prion (see ref and references therein) and APP (ref and references therein). These concentrations are many orders of magnitude larger than that inside the cell, where Cu, for instance, is present in negligible amount as an ion available to interactions. , The addressing of APP as a copper mediator has been discovered and lately associated to many neurodegenerative disorders. ,, Divalent cations change membrane structure, transport properties, − and reactivity, thus possibly promoting protein aggregates resembling ion channels and membrane pores. , Cu ions in contact with Aβ peptides form catalysts for the production of reactive oxygen species, activating dioxygen molecules, , and promoting oxidative pathways. − …”

Experimental methods in chemical engineering:X‐ray absorption spectroscopy—XAS,XANES,EXAFS

“…[94] Examples of the latter are proteins in complexes with transition metal ions, [95] as their oxidation state can change under radiation, [96] and because of chemical reactions with naturally abundant reducing agents. [97,98]…”