Identifying Trimerization Mechanisms of Human Islet Amyloid Polypeptide through Molecular Simulation

Human islet amyloid polypeptide (hIAPP, or human amylin) is implicated in the development of type II diabetes and is known to aggregate into amyloid fibrils. Early-stage aggregates have been shown to be cytotoxic, prompting study of prefibrillar oligomeric species and their aggregation mechanisms. Here, we build upon recent work that studied formation of the hIAPP dimer, which identified a dimerization pathway and its corresponding free energy profile, by studying and comparing hIAPP trimerization mechanisms. We use atomistic molecular dynamics simulations combined with the finite-temperature string method to identify favorable pathways for trimer formation, relevant intermediate structures, and free energy changes during trimerization. Specifically, we compare and contrast two trimerization scenarios: (1) formation of a trimer from three disordered hIAPP molecules, and (2) formation of a trimer from a single disordered hIAPP molecule added to an hIAPP dimer.