Substoichiometric aggregation inhibition of human islet amyloid polypeptide (IAPP), the hallmark of type 2 diabetes impacting millions of people, is crucial for developing clinic therapies, yet it remains challenging given that many candidate inhibitors require high doses. Intriguingly, insulin, the key regulatory polypeptide on blood glucose levels that are cosynthesized, costored, and cosecreted with IAPP by pancreatic β cells, has been identified as a potent inhibitor that can suppress IAPP amyloid aggregation at substoichiometric concentrations. Here, we computationally investigated the molecular mechanisms of the substoichiometric inhibition of insulin against the aggregation of IAPP and the incompletely processed IAPP (proIAPP) using discrete molecular dynamics simulations. Our results suggest that the amyloid aggregations of both IAPP and proIAPP might be disrupted by insulin through its binding with the shared amyloidogenic core sequences. However, the N-terminus of proIAPP competed with the amyloidogenic core sequences for the insulin interactions, resulting in attenuated inhibition by insulin. Moreover, insulin preferred to bind the elongation surfaces of IAPP seeds with fibril-like structure, with a stronger affinity than that of IAPP monomers. The capping of elongation surfaces by a small amount of insulin sterically prohibited the seed growth via monomer addition, achieving the substoichiometric inhibition. Together, our computational results provided molecular insights for the substoichiometric inhibition of insulin against IAPP aggregation, also the weakened effect on proIAPP. The uncovered substoichiometric inhibition by capping the elongation of amyloid seeds or fibrils may guide the rational designs of new potent inhibitors effective at low doses.
Keywords: Type 2 diabetes; amyloid aggregation; amyloid seed; discrete molecular dynamics; substoichiometric inhibition.