Resveratrol Inhibits the Formation of Multiple-Layered β-Sheet Oligomers of the Human Islet Amyloid Polypeptide Segment 22–27

Abstract

The abnormal self-assembly of a number of proteins or peptides is a hallmark of >20 amyloidogenic diseases. Recent studies suggest that the pathology of amyloidogenesis can be attributed primarily to cytotoxic, soluble, intermediate oligomeric species rather than to mature amyloid fibrils. Despite the lack of available structural information regarding these transient species, many therapeutic efforts have focused on inhibiting the formation of these aggregates. One of the most successful approaches has been to use small molecules, many of which have been found to inhibit toxic species with high efficacy. A significant issue that remains to be resolved is the mechanism underlying the inhibitory effects of these molecules. In this article, we present extensive replica-exchange molecular dynamics simulations to study the early aggregation of the human islet amyloid polypeptide segment 22–27 in the presence and absence of the small-molecule inhibitor resveratrol. The simulations indicate that aggregation of these peptides was hindered by resveratrol via a mechanism of blocking the lateral growth of a single-layered β-sheet oligomer (rather than preventing growth by elongation along the fibril axis). Intersheet side-chain stacking, especially stacking of the aromatic rings, was blocked by the presence of resveratrol molecules, and the overall aggregation level was reduced.