Dataset Information

Computational Study of Amyloidβ₄₂ Familial Mutations and Metal Interaction: Impact on Monomers and Aggregates Dynamical Behaviors.

ABSTRACT: One of the main hallmarks of Alzheimer's Disease is the formation of β-amyloid plaques, whose formation may be enhanced by metal binding or the appearance of familial mutations. In the present study, the simultaneous effect of familial mutations (E22Q, E22G, E22K, and D23N) and binding to metal ions (Cu(II) or Al(III)) is studied at the Aβ₄₂ monomeric and fibrillar levels. With the application of GaMD and MD simulations, it is observed that the effects of metal binding and mutations differ in the monomeric and fibrillar forms. In the monomeric structures, without metal binding, all mutations reduce the amount of α-helix and increase, in some cases, the β-sheet content. In the presence of Cu(II) and Al(III) metal ions, the peptide becomes less flexible, and the β-sheet content decreases in favor of forming α-helix motifs that stabilize the system through interhelical contacts. Regarding the fibrillar structures, mutations decrease the opening of the fiber in the vertical axis, thereby stabilizing the S-shaped structure of the fiber. This effect is, in general, enhanced upon metal binding. These results may explain the different Aβ₄₂ aggregation patterns observed in familial mutations.

SUBMITTER: Roldan-Martin L

PROVIDER: S-EPMC10934806 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Computational Study of Amyloidβ<sub>42</sub> Familial Mutations and Metal Interaction: Impact on Monomers and Aggregates Dynamical Behaviors.

Roldán-Martín Lorena L Sodupe Mariona M Maréchal Jean-Didier JD

Inorganic chemistry 20240226 10

One of the main hallmarks of Alzheimer's Disease is the formation of β-amyloid plaques, whose formation may be enhanced by metal binding or the appearance of familial mutations. In the present study, the simultaneous effect of familial mutations (E22Q, E22G, E22K, and D23N) and binding to metal ions (Cu(II) or Al(III)) is studied at the Aβ<sub>42</sub> monomeric and fibrillar levels. With the application of GaMD and MD simulations, it is observed that the effects of metal binding and mutations d ...[more]

PMID: 38408469

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Project description:Calcium ion regulation plays a crucial role in maintaining neuronal functions such as neurotransmitter release and synaptic plasticity. Copper (Cu2+ ) coordination to amyloid-β (Aβ) has accelerated Aβ1-42 aggregation that can trigger calcium dysregulation by enhancing the influx of calcium ions by extensive perturbing integrity of the membranes. Aβ1-42 aggregation, calcium dysregulation, and membrane damage are Alzheimer disease (AD) implications. To gain a detail of calcium ions' role in the full-length Aβ1-42 and Aβ1-42 -Cu2+ monomers contact, the cellular membrane before their aggregation to elucidate the neurotoxicity mechanism, we carried out 2.5 μs extensive molecular dynamics simulation (MD) to rigorous explorations of the intriguing feature of the Aβ1-42 and Aβ1-42 -Cu2+ interaction with the dimyristoylphosphatidylcholine (DMPC) bilayer in the presence of calcium ions. The outcome of the results compared to the same simulations without calcium ions. We surprisingly noted robust binding energies between the Aβ1-42 and membrane observed in simulations containing without calcium ions and is two and a half fold lesser in the simulation with calcium ions. Therefore, in the case of the absence of calcium ions, N-terminal residues of Aβ1-42 deeply penetrate from the surface to the center of the bilayer; in contrast to calcium ions presence, the N- and C-terminal residues are involved only in surface contacts through binding phosphate moieties. On the other hand, Aβ1-42 -Cu2+ actively participated in surface bilayer contacts in the absence of calcium ions. These contacts are prevented by forming a calcium bridge between Aβ1-42 -Cu2+ and the DMPC bilayer in the case of calcium ions presence. In a nutshell, Calcium ions do not allow Aβ1-42 penetration into the membranes nor contact of Aβ1-42 -Cu2+ with the membranes. These pieces of information imply that the calcium ions mediate the membrane perturbation via the monomer interactions but do not damage the membrane; they agree with the western blot experimental results of a higher concentration of calcium ions inhibit the membrane pore formation by Aβ peptides.

Dataset Information

Computational Study of Amyloidβ₄₂ Familial Mutations and Metal Interaction: Impact on Monomers and Aggregates Dynamical Behaviors.

Publications

Computational Study of Amyloidβ<sub>42</sub> Familial Mutations and Metal Interaction: Impact on Monomers and Aggregates Dynamical Behaviors.

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Dataset Information

Computational Study of Amyloidβ42 Familial Mutations and Metal Interaction: Impact on Monomers and Aggregates Dynamical Behaviors.

Publications

Computational Study of Amyloidβ<sub>42</sub> Familial Mutations and Metal Interaction: Impact on Monomers and Aggregates Dynamical Behaviors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Computational Study of Amyloidβ₄₂ Familial Mutations and Metal Interaction: Impact on Monomers and Aggregates Dynamical Behaviors.