Computational assessment of the impact of Cu(II) and Al(III) on β-amyloid42 fibrils: Binding sites, structural stability, and possible physiological implications

Abstract

One of Alzheimer’s disease major hallmarks is the aggregation of β-amyloid peptide, a process in which metal ions play an important role. In the present work, an integrative computational study has been performed to identify the metal-binding regions and determine the conformational impact of Cu(II) and Al(III) ion binding to the β-amyloid (Aβ42) fibrillary structure. Through classical and Gaussian accelerated molecular dynamics, it has been observed that the metal-free fiber shows a hinge fan-like motion of the S-shaped structure, maintaining the general conformation. Upon metal coordination, distinctive patterns are observed depending on the metal. Cu(II) binds to the flexible N-terminal region and induces structural changes that could ultimately disrupt the fibrillary structure. In contrast, Al(III) binding takes place with the residues Glu22 and Asp23, and its binding reinforces the core stability of the system. These results give clues on the molecular impact of the interaction of metal ions with the aggregates and sustain their non-innocent roles in the evolution of the illness.

Computational Study of Amyloidβ42 Familial Mutations and Metal Interaction: Impact on Monomers and Aggregates Dynamical Behaviors

“…Regarding the of the familial mutations on the fibrillar structures, the effect observed of metal binding is consistent with that reported in our previous study of the WT-Aβ 42 fibrillar form, 30 since Cu(II) interactions at the N Ter region of the fiber disrupt the characteristic tertiary structure of the fiber. In contrast, Al(III) binding further stabilizes the S-shape.…”

“…However, the calculation shows a lower amplitude, particularly for the E22G mutant (Figure 5) thereby indicating that the fibril is more rigid and less prone to disaggregate. To further analyze the changes induced by mutations in the tertiary structure of the fibers, and as done in our previous study, 30 the same five-distances analysis was applied to measure the compactness of the fiber (see Figure 6):…”

Addressing the gaps in homeostatic mechanisms of copper and copper dithiocarbamate complexes in cancer therapy: a shift from classical platinum-drug mechanisms

“…However, they often bind copper(II) in a square planar manner. 136,144 As shown in Fig. 6 (bottom) for component I, the copper(II) centre is coordinated to the N-terminal primary amine, two imidazole nitrogen (N) donor atoms from His-6 and His-13 or His-14, and the oxygen (O) donor atom from the backbone carbonyl group between asparagine 1 (Asp1) and alanine 2 (Ala2).…”

Influence of metal binding on the conformational landscape of neurofilament peptides

“…Whereas Roldan-Martin et al 81 established that aluminum complexes decrease helical content, leading to more extended structures with the appearance of transitory β-strands, Turner et al 82 claimed that helical conformations predominated along the simulations. More recently, the interaction of aluminum with Aβ-amyloid fibrils has been studied 83 showing that the binding to aluminum reinforces the core stability of these structures, supporting the idea that aluminum stabilizes neurotoxic species. 84,85…”

“…Alternatively, aggregation could occur by the interaction of preformed oligomers with the metals in line with the results of ref. 83 in the context of Aβ amyloid fibrils. The advantage of such a mechanism would be the lower configurational entropy penalty to include the metal in a preorganized oligomer, in which aluminum would interact through a mixture of phosphorylated serine and acidic residues belonging to different chains.…”