Physics Colloquium - Inhibiting Protein Amyloid Aggregation with Nanoparticles

Protein amyloid aggregation is associated with an increasing list of human diseases, including Amyotrophic Lateral Sclerosis, Alzheimer’s Diseases and Type-2 Diabetes (T2D). The hallmark of various amyloid diseases is the deposition of amyloid fibrils in human tissues formed by various disease-associated proteins. Despite differences in precursor protein sequences and structures, the final amyloid fibrils share the common cross-beta structure. Recent studies also show that aggregation intermediates rather than the final fibrils are cytotoxic. Rapid advances in nanotechnology and nanomedicine open the opportunity of engineered nanoparticles that may be used to inhibit protein aggregation mediated cytotoxicity. In collaborations with experimental groups, we have established that PAMAM dendrimer, Graphene Oxide, and a class of star-shaped polymer nanostructures – nanomaterials with many applications such as drug loading, and biosensing – have also anti-amyloid aggregation activities against the human islet amyloid polypeptide (hIAPP), aggregation of which is implicated in T2D. Our computational studies revealed that anti-amyloid activities can be achieved by either the inhibition of self-association or the acceleration of fibrillization, both of which reduce the accumulation of toxic intermediates. To fully understand the complex effects of NPs on protein aggregation, including both aggregation inhibitions as observed in our studies and/or aggregation promotions reported by others, we devised a simple coarse-grained model to study peptide aggregation in the presence of NPs. Our systematic computational study offers a molecular mechanism for delineating the contrasting and seemingly conflicting effects of NP-protein attraction on amyloid aggregation and highlights the potential of tailoring anti-aggregation nanomedicine against amyloid diseases.