Abstract
Understanding how small molecules interface amyloid fibrils on the nanoscale is of importance for developing therapeutic treatment against amyloid-based diseases. Here we show, for the first time, that human islet amyloid polypeptide (IAPP) in the fibrillar form is polymorphic and ambidextrous possessing multiple periodicities. Upon interfacing with small molecule epigallocatechin gallate (EGCG), IAPP aggregation was rendered off pathway assuming the form of soft and disordered clusters, while mature IAPP fibrils displayed kinks and branching but conserved the twisted fibril morphology. These nanoscale phenomena resulted from competitive interactions between EGCG and the IAPP amyloidogenic region, as well as end capping of the fibrils by the small molecule. This information is crucial to delineating IAPP toxicity implicated in type 2 diabetes and developing new inhibitors against amyloidogenesis.