Exploring the structure and stability of pentameric amyloid β peptide aggregates in aqueous ammonium-based ionic liquid solutions

The self-assembly of amyloid beta (Aβ) proteins into fibrils is linked to Alzheimer's disease (AD). Soluble pentamers, particularly those formed in the early stages of Aβ aggregation, are considered highly neurotoxic. This study uses molecular dynamics simulations to explore how trimethylammonium chloride (TMAC), cholinium chloride (ChoC), and tetrabutylammonium chloride (TBAC) ionic liquids (ILs) affect the conformational stability and the association mechanism of Aβ pentameters. These ILs, characterized by varying hydrophilicity/hydrophobicity, exert differential effects on the conformatioanl flexibility of Aβ pentameters. Computational analyses reveal that TBAC induces greater conformational flexibility and multiple energetically favorable states for the Aβ pentamer, potentially driving the pentamerization process along various pathways to form different polymorphic Aβ fibrillar structures. Moreover, analysis of solvent distributions demonstrates that exchange of water by IL ion pairs at the pentamer's exterior surface primarily occurs beyond the first layer of surface-bound water molecules. Particularly, hydrophobic TBA cations show an enhanced propensity to replace weakly interacting water molecules on the surface. Mechanistic insights derived from umbrella sampling simulations further elucidate how ILs modulate the association/dissociation of Aβ monomers within pentameric aggregates. Our findings indicate that the binding of the Aβ peptide becomes less favorable and the binding free energy decreases when transitioning from TMAC to TBAC solutions, as compared to a pure aqueous solution. Finally, energy landscape analysis of Aβ peptide docking to Aβ pentameters reveals multiple low-energy conformations, which are more dispersed in the presence of ChoC and TBAC solutions, potentially hindering Aβ prefibril growth.