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

Abstract

Multiple microsecond-length molecular dynamics simulations of complexes of Al(III) with amyloid-β (Aβ) peptides of varying length are reported, employing a non-bonded model of Al-coordination to the peptide, which is modelled using the AMBER ff14SB forcefield. Individual simulations reach equilibrium within 100 to 400 ns, as determined by root mean square deviations, leading to between 2.1 and 2.7 μs of equilibrated data. These reveal a compact set of configurations, with radius of gyration similar to that of the metal free peptide but larger than complexes with Cu, Fe and Zn. Strong coordination through acidic residues Glu3, Asp7 and Glu11 is maintained throughout all trajectories, leading to average coordination numbers of approximately 4 to 5. Helical conformations predominate, particularly in the longer Al-Aβ40 and Al-Aβ42 peptides, while β-strand forms are rare. Binding of the small, highly charged Al(III) ion to acidic residues in the N-terminus strongly disrupts their ability to engage in salt bridges, whereas residues outside the metal binding region engage in salt bridges to similar extent to the metal-free peptide, including the Asp23-Lys28 bridge known to be important for formation of fibrils. High helical content and disruption of salt bridges leads to characteristic tertiary structure, as shown by heat maps of contact between residues as well as representative clusters of trajectories.

Molecular mechanisms of aluminum neurotoxicity: Update on adverse effects and therapeutic strategies

“…Pioneer studies by Exley et al (1993) and Kawahara et al (1994) demonstrated direct interaction between Al and amyloid β with increasing aggregation of the latter. Later studies have unraveled the particular features of Al-amyloid β interaction and its effects on the protein structure (Narayan et al, 2013;Turner et al, 2019). Particularly, Al(III) is capable of inducing β-sheet formation and subsequent aggregation of Aβ40 .…”

Aluminium Binding to Modified Amyloid-β Peptides: Implications for Alzheimer’s Disease

“…The Al-induced flexibility allows for significant quantities of helical secondary structure to develop. Indeed, such metal ions affect residues 11–20 and 26–36 [ 23 ]. Salt bridges are strongly affected by the presence of the Al ion in the 11–16 region, as we demonstrated here.…”

“…Recently, multiple microsecond-long molecular dynamics simulations of complexes of amyloid-β peptides with aluminium ions have also been reported [ 23 ]. On the other hand, in order to highlight the importance of each amino acid residue from the Aβ region involved in the formation of complexes with amyloidogenic substances, peptides containing alanine single-site mutations within the Aβ binding sequence can be produced by solid-phase peptide synthesis, whereas the complex formation could be investigated for each mutant peptide by mass spectrometry (MS) [ 24 ].…”

“…Consequently, the modified peptides Aβ (1–16) A 3 6,13,14 (H- 1 DAEFR A DSGYEV AA QK 16 -NH 2 ) and Aβ (1–16) S 3 6,13,14 (H- 1 DAEFR S DSGYEV SS QK 16 -NH 2 ) were synthesised by the Fmoc/ t Bu solid-phase peptide synthesis (SPPS) strategy and purified by reverse phase-high performance liquid chromatography (RP-HPLC). Furthermore, because the amino acid residues Glu 3 , Asp 7 , and Glu 11 are suspected to bind Al [ 23 ], we decided to use in our experiments the smaller peptide Aβ (9–16) and several analogues, which do not contain the first two amino acid residues in their sequences. Consequently, in the sequence of the Aβ (9–16) peptide fragment (GYEVHHQK), we replaced either the histidine residues or the tyrosine one with glycine to form new molecules of more flexible peptides, namely Aβ (9–16) G 1 10 , (G G EVHHQK), Aβ (9–16) G 2 13,14 (GYEV GG QK), and Aβ (9–16) G 3 10,13,14 (G G EV GG QK).…”

Docking studies and molecular dynamics simulations of the binding characteristics of waldiomycin and its methyl ester analog to Staphylococcus aureus histidine kinase

“…Lastly, MD simulations of 10 ns were processed at 1 atm and 298.15 K under the NPT ensemble with a time step of two femtoseconds (fs). The covalent bonds with hydrogen atoms were constrained by the use of the SHAKE algorithm [27] and Langevin dynamics were used to control the system temperature. Throughout the MD simulations, all of the atom coordinates of the system were saved every 1 ps.…”