A Small Molecule\nImpedes the Aβ<sub>1–42</sub> Tetramer Neurotoxicity\nby Preserving Membrane Integrity: Microsecond\nMultiscale Simulations

Amyloid-β (Aβ<sub>1–42</sub>) peptides\naggregated\ninto plaques deposited in the brain are the main hallmark of Alzheimer’s\ndisease (AD), a social and economic burden worldwide. In this context,\ninsoluble Aβ<sub>1–42</sub> fibrils are the main components\nof plaques. The recent trials that used approved AD drugs show that\nthey can remove the fibrils from AD patients’ brains, but they\ndid not halt the course of the disease. Mounting evidence envisages\nthat the soluble Aβ<sub>1–42</sub> oligomers’\ninteractions with the neuronal membrane trigger higher cell death\nthan Aβ<sub>1–42</sub> fibril interactions. Developing\na compound that can alleviate the oligomer’s toxicity is one\nof the most demanding tasks for curing the disease. We performed two\nmolecular dynamics (MD) simulations in an explicit solvent model.\nIn the first case, 55-μs of multiscale all-atom (AA)/coarse-grained\n(CG) MD simulations were carried out to decipher the impact of a previously\ndescribed small anti-Aβ molecule, termed M30 (2-octahydroisoquinolin-2(1H)-ylethanamine),\non an Aβ<sub>1–42</sub> tetramer structure in close contact\nwith a DMPC bilayer. In the second case, 15-μs AA/CG MD simulations\nwere performed to rationalize the dynamics between Aβ<sub>1–42</sub> and Aβ<sub>1–42</sub>-M30 tetramer complexes embedded\nin DMPC. On the membrane bilayer, we found that the Aβ<sub>1–42</sub> tetramer penetrates the bilayer surface due to unrestricted conformational\nflexibility and many contacts with the membrane phosphate groups.\nIn contrast, no Aβ<sub>1–42</sub>-M30 tetramer penetration\nwas observed during the entire course of the simulation. In the case\nof the membrane-embedded Aβ<sub>1–42</sub> tetramer,\nthe integrity of the bottom bilayer leaflet was severely affected\nby the interactions between the negatively charged phosphate groups\nand the positively charged residues of the Aβ<sub>1–42</sub> tetramer, resulting in a deep tetramer penetration into the bilayer\nhydrophobic region. These contacts were not observed in the case of\nthe membrane-embedded Aβ<sub>1–42</sub>-M30 tetramer.\nIt was noted that M30 molecules bind to Aβ<sub>1–42</sub> tetramer through hydrogen bonds, resulting in a conformational stable\nAβ<sub>1–42</sub>-M30 complex. The associated complex\nhas reduced conformational changes and an enhanced rigidity that prevents\nthe tetramer dissociation by interfering with the tetramer-membrane\ncontacts. Our findings suggest that the M30 molecules could bind to\nAβ<sub>1–42</sub> tetramer resulting in a rigid structure,\nand that such complexes do not significantly perturb the membrane\nbilayer organization. These observations support the <i>in vitro</i> and <i>in vivo</i> experimental evidence that the M30\nmolecules prevent synaptotocity, improving AD-affected mice memory.