In Silico Probing Ca2+ and Zn2+ Permeable Transmembrane 4Aβ1-42 Barrel

Alzheimer’s disease (AD) is known as one of the most popular forms of dementia affecting numerous people worldwide. The Amyloid beta (Aβ) peptides form oligomeric conformations that cause the intracellular Ca²⁺ and Zn²⁺ abnormality leading to the death of neuron cells. The failure of AD therapy targeting Aβ oligomers probably caused by misunderstanding the ions transport through transmembrane Aβ (tmAβ) ion-like channel since Aβ oligomers transiently exist in a mixture environment involving various order of Aβ oligomers. The high-resolution of tmAβ peptides are thus unavailable until the date. Fortunately, computational approaches are able to complement the missing experimental structures. The transmembrane 4Aβ_1-42 (tm4Aβ_1-42) barrel, one of the most neurotoxic elements, was thus predicted in the previous work. Therefore, in this context, the Ca²⁺/Zn²⁺ ions transport through the tm4Aβ_1-42 barrel was investigated by using the fast pulling of ligand (FPL) and umbrella sampling (US) methods. Good consistent results were obtained implying that Ca²⁺ ion transport through tm4Aβ_1-42 barrel with a lower free energy barrier compared with Zn²⁺ ion. The obtained results about Ca²⁺/Zn²⁺ transport across tmAβ_1-42 barrel probably enhances the AD therapy since we can design an inhibitor is able to block the transport.