A Small Molecule Impedes the Aβ1–42 Tetramer Neurotoxicity by Preserving Membrane Integrity: Microsecond Multiscale Simulations

Amyloid-β (Aβ1–42) peptides aggregated into plaques deposited in the brain are the main hallmark of Alzheimer’s disease (AD), a social and economic burden worldwide. In this context, insoluble Aβ1–42 fibrils are the main components of plaques. The recent trials that used approved AD drugs show that they can remove the fibrils from AD patients’ brains, but they did not halt the course of the disease. Mounting evidence envisages that the soluble Aβ1–42 oligomers’ interactions with the neuronal membrane trigger higher cell death than Aβ1–42 fibril interactions. Developing a compound that can alleviate the oligomer’s toxicity is one of the most demanding tasks for curing the disease. We performed two molecular dynamics (MD) simulations in an explicit solvent model. In the first case, 55-μs of multiscale all-atom (AA)/coarse-grained (CG) MD simulations were carried out to decipher the impact of a previously described small anti-Aβ molecule, termed M30 (2-octahydroisoquinolin-2­(1H)-ylethanamine), on an Aβ1–42 tetramer structure in close contact with a DMPC bilayer. In the second case, 15-μs AA/CG MD simulations were performed to rationalize the dynamics between Aβ1–42 and Aβ1–42-M30 tetramer complexes embedded in DMPC. On the membrane bilayer, we found that the Aβ1–42 tetramer penetrates the bilayer surface due to unrestricted conformational flexibility and many contacts with the membrane phosphate groups. In contrast, no Aβ1–42-M30 tetramer penetration was observed during the entire course of the simulation. In the case of the membrane-embedded Aβ1–42 tetramer, the integrity of the bottom bilayer leaflet was severely affected by the interactions between the negatively charged phosphate groups and the positively charged residues of the Aβ1–42 tetramer, resulting in a deep tetramer penetration into the bilayer hydrophobic region. These contacts were not observed in the case of the membrane-embedded Aβ1–42-M30 tetramer. It was noted that M30 molecules bind to Aβ1–42 tetramer through hydrogen bonds, resulting in a conformational stable Aβ1–42-M30 complex. The associated complex has reduced conformational changes and an enhanced rigidity that prevents the tetramer dissociation by interfering with the tetramer-membrane contacts. Our findings suggest that the M30 molecules could bind to Aβ1–42 tetramer resulting in a rigid structure, and that such complexes do not significantly perturb the membrane bilayer organization. These observations support the in vitro and in