Amyloid fibrils were considered a major culprit for cell degeneration till the 1990s. [5] Recent studies, however, have implicated the oligomers as the most toxic species. This toxicity is believed to arise from the interactions of the oligomers with cell membranes, proteins, chaperones, organelles, biometals, and small ligands to induce membrane damage, endoplasmic reticulum stress, and reactive oxygen species (ROS) [6] (Figure 1). The ambiguity surrounding the exact cause of oligomer toxicity originates from the transient and heterogeneous nature of the aggregation species, compounded by the coexistence of primary and secondary nucleation, [7] the kinetics of fibrillar association, dissociation, and fragmentation, and the polymorphism of amyloid fibrils, driven by thermodynamic transitions. It has now been verified that the crystalline form, rather than the fibrils, is the most stable state of amyloid proteins. [8] Here, we outline the biophysical foundation of amyloid aggregation, and summarize current mitigation strategies involving nanomaterial and multifunctional nanomaterial composite inhibitors in silico, in vitro, and in vivo. We note the occasional divergence between protein aggregation and toxicity, and discuss the implications of the protein "corona" [9] enriched on amyloid fibrils in a biological milieu. This presentation highlights the structural and physicochemical attributes of nanomaterials and multifunctional nanocomposites for targeting amyloidosis. In Silico Mitigation of Amyloidosis with NanomaterialsUnderstanding the aggregation pathways and uncovering the structures and dynamics of oligomeric intermediates are crucial for the design of antiamyloid strategies. The heterogeneous and Amyloidosis is a biophysical phenomenon of protein aggregation with biological and pathogenic implications. Among the various strategies developed to date, nanomaterials and multifunctional nanocomposites possessing certain structural and physicochemical traits are promising candidates for mitigating amyloidosis in vitro and in vivo. The mechanisms underpinning protein aggregation and toxicity are introduced, and opportunities in materials science to drive this interdisciplinary field forward are highlighted. Advancement of this emerging frontier hinges on exploitation of protein self-assembly and interactions of amyloid proteins with nanoparticles, intracellular and extracellular proteins, chaperones, membranes, organelles, and biometals.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.

Small oligomers formed early along human islet amyloid polypeptide (hIAPP) aggregation is responsible for the cell death in Type II diabetes. The epigallocatechin gallate (EGCG), a green tea extract, was found to inhibit hIAPP fibrillation. However, the inhibition mechanism and the conformational distribution of the smallest hIAPP oligomer – dimer are mostly unknown. Herein, we performed extensive replica exchange molecular dynamic simulations on hIAPP dimer with and without EGCG molecules. Extended hIAPP dimer conformations, with a collision cross section value similar to that observed by ion mobility-mass spectrometry, were observed in our simulations. Notably, these dimers adopt a three-stranded antiparallel β-sheet and contain the previously reported β-hairpin amyloidogenic precursor. We find that EGCG binding strongly blocks both the inter-peptide hydrophobic and aromatic-stacking interactions responsible for inter-peptide β-sheet formation and intra-peptide interaction crucial for β-hairpin formation, thus abolishes the three-stranded β-sheet structures and leads to the formation of coil-rich conformations. Hydrophobic, aromatic-stacking, cation-π and hydrogen-bonding interactions jointly contribute to the EGCG-induced conformational shift. This study provides, on atomic level, the conformational ensemble of hIAPP dimer and the molecular mechanism by which EGCG inhibits hIAPP aggregation.

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