Transition Metal Ion Interactions with Disordered Amyloid-β Peptides in the Pathogenesis of Alzheimer’s Disease: Insights from Computational Chemistry Studies

Abstract

Monomers and oligomers of the amyloid-β peptide aggregate to form the fibrils found in the brains of Alzheimer’s disease patients. These monomers and oligomers are largely disordered and can interact with transition metal ions, affecting the mechanism and kinetics of amyloid-β aggregation. Due to the disordered nature of amyloid-β, its rapid aggregation, as well as solvent and paramagnetic effects, experimental studies face challenges in the characterization of transition metal ions bound to amyloid-β monomers and oligomers. The details of the coordination chemistry between transition metals and amyloid-β obtained from experiments remain debated. Furthermore, the impact of transition metal ion binding on the monomeric or oligomeric amyloid-β structures and dynamics are still poorly understood. Computational chemistry studies can serve as an important complement to experimental studies and can provide additional knowledge on the binding between amyloid-β and transition metal ions. Many research groups conducted first-principles calculations, ab initio molecular dynamics simulations, quantum mechanics/classical mechanics simulations, and classical molecular dynamics simulations for studying the interplay between transition metal ions and amyloid-β monomers and oligomers. This review summarizes the current understanding of transition metal interactions with amyloid-β obtained from computational chemistry studies. We also emphasize the current view of the coordination chemistry between transition metal ions and amyloid-β. This information represents an important foundation for future metal ion chelator and drug design studies aiming to combat Alzheimer’s disease.

Zinc binding promotes greater hydrophobicity inAlzheimer's Aβ42peptide than copper binding: Molecular dynamics and solvation thermodynamics studies

“…In this respect, the details of the coordination chemistry between Zn 2+ /Cu 2+ and Aβ have been extensively studied over the last two decades using a number of spectroscopic techniques, such as electron paramagnetic resonance, nuclear magnetic resonance (NMR), solid state NMR, circular dichroism, X-ray absorption spectroscopy, electrospray-ionization mass spectroscopy, and Raman spectroscopy, and computer simulations. [12][13][14][15][16][17] In general, a high affinity between metals and a peptide was found in the N-terminal region of 1-16 amino acids (Aβ 1-16 ). At physiological pH, the most acceptable binding mode for Zn 2+ is 3N2O, which involves three nitrogen atoms (3 N) from His6, His13, and His14 residues, and two oxygen atoms (2O) from Glu11 residue.…”

“…At physiological pH, the most acceptable binding mode for Zn 2+ is 3N2O, which involves three nitrogen atoms (3 N) from His6, His13, and His14 residues, and two oxygen atoms (2O) from Glu11 residue. 12,14 The most commonly accepted coordination mode for Cu 2+ is the 3N1O, which includes three nitrogen atoms from Asp1, His6, and His13 residues, and one oxygen atom from Asp1 residue. 12,17,18 These coordination modes have been used in our current work as a metal binding template, while the exact coordination modes are still under debate.…”

“…12,14 The most commonly accepted coordination mode for Cu 2+ is the 3N1O, which includes three nitrogen atoms from Asp1, His6, and His13 residues, and one oxygen atom from Asp1 residue. 12,17,18 These coordination modes have been used in our current work as a metal binding template, while the exact coordination modes are still under debate. 17 Recently, X-ray crystallography 12 was unable to determine the structure of metal-Aβ complex, while several spectroscopic studies can provide only limited information.…”

A New Fluorescent Sensor for Fe3+ Based on Glycoluril Molecular Clip

“…Most of the time, the detection methods of host‐guest recognition are mainly through H NMR titration. Design and synthesis of fluorescence sensor to recognize and response to heavy and transition metal ions continue to be an area of interest in supramolecular chemistry because they play a significant role in chemical industry, biological metabolism and environmental protection . The study of supramolecular host compounds in fluorescent sensors has received wide attention in recent years.…”

The investigation of 2D monolayers as potential chelation agents in Alzheimer’s disease

“…To resolve this ambiguity, recent research efforts have emphasized determining the metal-Aβ binding sites by identifying the coordination point at which the metal ion binds to the amino acid residues (Del Barrio et al (2017)). Researchers have developed at least three investigational approaches: 1) absorption spectroscopy computational methods; 2), x-ray methods; and first-principles computations (Strodel and Coskuner-Weber (2019)).…”