Inhibition of Aß16-22 Aggregation by [TEA]+[Ms]- Follows Weakening of the Hydrophobic Core and Sequestration of Peptides in Ionic Liquid Nanodomains.

We developed a coarse-grained model for the protic ionic liquid, triethylammonium mesylate ([TEA]+[Ms]-), to characterize its inhibitory effects on amyloid aggregation using the K16LVFFAE22 fragment of the amyloid-ß (Aß16-22) as a model amyloidogenic peptide. In agreement with previous experiments, coarse-grained molecular dynamics simulations showed that increasing concentrations of [TEA]+[Ms]- in aqueous media led to increasingly small Aß16-22 aggregates with low beta-sheet contents. The cause of [TEA]+[Ms]-'s inhibition of peptide aggregation was found to be a result of two interrelated effects. At a local scale, the enrichment of interactions between [TEA]+ cations and hydrophobic phenylalanine side chains weakened the hydrophobic cores of amyloid aggregates, resulting in poorly ordered structures. At a global level, peptides tended to localize at the interfaces of IL-rich nanostructures with water. At high IL concentrations, when the IL-water interface was large or fragmented, Aß16-22 peptides were dispersed in the simulation cell, sometimes sequestered at unaggregated monomeric states. Together, these phenomena underlie [TEA]+[Ms]-'s inhibition of amyloid aggregation. This work addresses the critical lack of knowledge on the mechanisms of protein-ionic liquid interactions and may have broader implications for industrial applications.

Unravelling heparin's enhancement of amyloid aggregation in a model peptide system.

A coarse-grained (CG) model for heparin, an anionic polysaccharide, was developed to investigate the mechanisms of heparin's enhancement of fibrillation in many amyloidogenic peptides. CG molecular dynamics simulations revealed that heparin, by forming contacts with the model amyloidogenic peptide, amyloid-ß's K16LVFFAE22 fragment (Aß16-22), promoted long-lived and highly beta-sheet-like domains in the peptide oligomers. Concomitantly, heparin-Aß16-22 contacts suppressed the entropy of mixing of the oligomers' beta-domains. Such oligomers could make better seeds for fibrillation, potentially contributing to heparin's fibril-enhancing behaviour. Additionally, reductions in heparin's flexibility led to delayed aggregation, and less ordered Aß16-22 oligomers, thus offering insights into the contrasting inhibition of fibrillation by the relatively rigid polysaccharide, chitosan.

Mechanistic insights into the inhibition of amyloid-ß aggregation by chitosan.

Neurodegeneration related to Alzheimer's disease has long been linked to the accumulation of abnormal aggregates of amyloid-ß (Aß) peptides. Pre-fibrillar oligomeric intermediates of Aß aggregation are considered the primary drivers of neurotoxicity, however, their targetting remains an unresolved challenge. In response, the effects of macromolecular components of the blood-brain barrier, artificial extracellular matrix mimics, and polymeric drug delivery particles, on the aggregation of Aß peptides are gaining interest. Multiple experimental studies have demonstrated the potential of one such macromolecule, chitosan (CHT) - a polysaccharide with acid induced cationicity (pKa 6.5) - to inhibit the aggregation of Aß, and reduce the associated neurotoxic effects. However, the mechanistic details of this inhibitory action, and the structural details of the emergent Aß complexes are not understood. In this work, we probed how CHT modulated the aggregation of Aß's central hydrophobic core fragment, K16LVFFAE22, using coarse-grained molecular dynamics simulations. CHT was found to bind and sequester Aß peptides, thus limiting their ultimate aggregation numbers. The intensity of this inhibitory action was enhanced by CHT concentration, as well as CHT's pH-dependent degree of cationicity, corroborating experimental observations. Furthermore, CHT was found to reshape the conformational landscapes of Aß peptides, enriching collapsed peptides at near-physiological conditions of pH 7.5, and extended peptides at slightly acidic conditions of pH 6.5, where the charge profile of K16LVFFAE22 peptides remained unchanged. These conformational changes were limited to peptides in direct contact in CHT, thus emphasizing the influence of local environments on Aß conformations. These findings add to basic knowledge of the aggregation behaviour of Aß peptides, and could potentially guide the development of advanced CHT-based materials for the treatment of Alzheimer's disease.