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

Front Neurosci. 2023 Feb 6:17:1110311. doi: 10.3389/fnins.2023.1110311. eCollection 2023.

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.

Keywords: amyloid Aβ-42; metal; molecular dynamic (MD); molecular modeling and simulation; protein-ligand docking.

Grants and funding

This work was supported by the projects PID2020-116861GB-I00 and PID2020-112715GB-I00 from the Spanish Ministerio de Ciencia y Educación. LR-M would like to thank Generalitat de Catalunya (grant 2020FI_B2_01000).