Calcium inhibits penetration of Alzheimer's Aβ - monomers into the membrane.

Calcium ion regulation plays a crucial role in maintaining neuronal functions such as neurotransmitter release and synaptic plasticity. Copper (Cu ) coordination to amyloid-β (Aβ) has accelerated Aβ aggregation that can trigger calcium dysregulation by enhancing the influx of calcium ions by extensive perturbing integrity of the membranes. Aβ aggregation, calcium dysregulation, and membrane damage are Alzheimer disease (AD) implications. To gain a detail of calcium ions' role in the full-length Aβ and Aβ -Cu 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 Aβ and Aβ -Cu 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 Aβ 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 Aβ 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, Aβ -Cu actively participated in surface bilayer contacts in the absence of calcium ions. These contacts are prevented by forming a calcium bridge between Aβ -Cu and the DMPC bilayer in the case of calcium ions presence. In a nutshell, Calcium ions do not allow Aβ penetration into the membranes nor contact of Aβ -Cu 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.

© 2022 The Authors. Proteins: Structure, Function, and Bioinformatics published by Wiley Periodicals LLC.