Inhibition of Aβ<sub>16–22</sub> Aggregation\nby [TEA]<sup>+</sup>[Ms]<sup>−</sup> Follows Weakening of the\nHydrophobic Core and Sequestration of Peptides in Ionic Liquid Nanodomains

We developed a coarse-grained model for the protic ionic\nliquid,\ntriethylammonium mesylate ([TEA]<sup>+</sup>[Ms]<sup>−</sup>), to characterize its inhibitory effects on amyloid aggregation\nusing the K<sub>16</sub>LVFFAE<sub>22</sub> fragment of the amyloid-β\n(Aβ<sub>16–22</sub>) as a model amyloidogenic peptide.\nIn agreement with previous experiments, coarse-grained molecular dynamics\nsimulations showed that increasing concentrations of [TEA]<sup>+</sup>[Ms]<sup>−</sup> in aqueous media led to increasingly small\nAβ<sub>16–22</sub> aggregates with low beta-sheet contents.\nThe cause of [TEA]<sup>+</sup>[Ms]<sup>−</sup>’s inhibition\nof peptide aggregation was found to be a result of two interrelated\neffects. At a local scale, the enrichment of interactions between\n[TEA]<sup>+</sup> cations and hydrophobic phenylalanine side chains\nweakened the hydrophobic cores of amyloid aggregates, resulting in\npoorly ordered structures. At a global level, peptides tended to localize\nat the interfaces of IL-rich nanostructures with water. At high IL\nconcentrations, when the IL–water interface was large or fragmented,\nAβ<sub>16–22</sub> peptides were dispersed in the simulation\ncell, sometimes sequestered at unaggregated monomeric states. Together,\nthese phenomena underlie [TEA]<sup>+</sup>[Ms]<sup>−</sup>’s\ninhibition of amyloid aggregation. This work addresses the critical\nlack of knowledge on the mechanisms of protein–ionic liquid\ninteractions and may have broader implications for industrial applications.