Herpes Simplex Virus Glycoprotein D Associated with Aβ ₁–₄₂ Tetramers Mediates Neurotoxicity by Perturbing Neuronal Membrane Integrity: A Molecular Dynamics Simulation

Alzheimer's disease (AD) is characterized by deleterious amyloid plaques deposited in the brain, formed through the interaction of Amyloid β-peptides (Aβ₁₋₄₂) with the cell membrane. Despite promising preclinical results, Aβ₁₋₄₂ aggregation inhibitors have not delivered the anticipated benefits in clinical trials for AD. This discrepancy may stem from the fact that the cause of sporadic AD is unknown. Mounting evidence suggests that herpes simplex virus type-1 (HSV-1) may significantly contribute to the onset of AD by facilitating the aggregation of Aβ₁₋₄₂ into oligomers, leading to neurotoxicity and neuronal cell loss in the brain. However, the mechanism of neurotoxicity remains elusive. Understanding the relationship between the HSV-1 envelope glycoprotein D (gD) and Aβ₁₋₄₂ oligomers and their impact on neuronal membranes, is the most demanding task for unveiling the underlying mechanism. Thus, we performed extensive all-atom molecular dynamics (MD) simulations to thoroughly investigate the molecular mechanism underlying the interaction between the gD protein and Aβ₁₋₄₂ oligomers in both aqueous environments and in the presence of lipid bilayers, which mimic the composition of neuronal membranes in vivo. Our simulation study provides valuable insights into the initial stages of this process, in which the Aβ₁₋₄₂ tetramer (Aβ₁₋₄₂t) associates with gD via hydrogen bonds formed at their interface. Consequently, we observed that Aβ₁₋₄₂t-gD, rather than Aβ₁₋₄₂t alone, demonstrates significant adsorption to the membrane, driven by robust electrostatic interactions between the charged residues of Aβ₁₋₄₂t-gD and the phosphate groups of lipids such as POPC, POPS, POPE, and PSM. This interaction significantly reduces the electrostatic and van der Waals interactions among the lipids, in contrast to Aβ₁₋₄₂t binding alone. As a result, disruptions of the lipid membrane integrity are more pronounced upon the Aβ₁₋₄₂t-gD binding than the Aβ₁₋₄₂t alone. This study provides atomic-level evidence that gD amplifies Aβ₁₋₄₂t-membrane interactions, potentially altering membrane phase behavior and contributing to the initial molecular events underlying neuronal dysfunction, thereby suggesting a link between HSV-1 infection and the pathogenesis of AD.