Metal Binding to Amyloid-β_1–42: A Ligand Field Molecular Dynamics Study

Abstract

Ligand field molecular mechanics simulation has been used to model the interactions of copper(II) and platinum(II) with the amyloid-β peptide monomer. Molecular dynamics over several microseconds for both metalated systems are compared to analogous results for the free peptide. Significant differences in structural parameters are observed, both between Cu and Pt bound systems as well as between free and metal-bound peptide. Both metals stabilize the formation of helices in the peptide as well as reducing the content of β secondary structural elements compared to the unbound monomer. This is in agreement with experimental reports of metals reducing β-sheet structures, leading to formation of amorphous aggregates over amyloid fibrils. The shape and size of the peptide structures also undergo noteworthy change, with the free peptide exhibiting globular-like structure, platinum(II) system adopting extended structures, and copper(II) system resulting in a mixture of conformations similar to both of these. Salt bridge networks exhibit major differences: the Asp23-Lys28 salt bridge, known to be important in fibril formation, has a differing distance profile within all three systems studied. Salt bridges in the metal binding region of the peptide are strongly altered; in particular, the Arg5-Asp7 salt bridge, which has an occurrence of 71% in the free peptide, is reduced to zero in the presence of both metals.

On the Conformational Dynamics of β-Amyloid Forming Peptides: A Computational Perspective

“…Their results demonstrated a structural similarity to the models of highly ordered aggregates, suggesting that these hairpins may act as seeds for Aβ assembly. Temperature-REMD (T-REMD) and Hamiltonian-REMD (H-REMD) are widely used for the study of simulations of aggregation from random states (Côté et al, 2012;Ayton et al, 2013;Mutter et al, 2018) and the interaction of non-Aβ amyloid component and Aβ. Meng et al (2018) employed single-molecule Förster resonance energy transfer spectroscopy with site-specific dye labeling using an unnatural amino acid and REMD simulations to investigate conformations and dynamics of Aβ isoforms, Aβ40 and Aβ42.…”

“…The study by Miller et al sheds light on the role of the metal ions, known as toxic agents, in stabilizing the amyloid oligomers, which is consistent with clinical observations that high concentrations of metal ions are found in patients suffering from neurodegenerative disease. Another study used the ligand field molecular mechanics simulation to model the interactions of copper and platinum with the Aβ 1-42 peptide monomer (Mutter et al, 2018). The results of molecular dynamics simulation over several microseconds were compared to analogous results for the free peptide.…”

Molecular dynamics simulation of aluminium binding to amyloid-β and its effect on peptide structure

“…Root mean square displacement (RMSD) relative to the starting structures was used as a measure of equilibration. [9,46] Fig 1 shows RMSD plots for all backbone atoms in Al-Aβ16, Al-Aβ40 and Al-Aβ42 systems, respectively, relative to their respective minimised structures. Equilibration points are shown in Table 1; Al-Aβ16 simulations reach stable values rapidly, while Al-Aβ40 and Al-Aβ42 simulations take longer to equilibrate.…”

Replica exchange molecular dynamics simulation of the coordination of Pt(ii)-Phenanthroline to amyloid-β

“…It is clear from this that Pt-coordinated Ab forms numerous and stable helical structures, rather more than is found for other metals. 59 It may be that this preference for helical structure is related to the known inhibition of bril formation induced by a C a -C a distances in Pt-Ab16 and Pt-Ab42 are used to interrogate the tertiary structure of the peptides, as represented in the contact maps in Fig. 2.…”