Computational assessment of the impact of Cu(II) and Al(III) on β-amyloid 42 fibrils: Binding sites, structural stability, and possible physiological implications

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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 (Aβ) 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.
Original languageEnglish
Article number1110311
JournalFrontiers in Neuroscience
Volume17
DOIs
Publication statusPublished - 6 Feb 2023

Keywords

  • Molecular modeling and simulation
  • Molecular dynamic (MD)
  • Amyloid Aβ-42
  • Protein-ligand docking
  • Metal

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