Human Islet Amyloid Polypeptide: Identifying Early-Stage Aggregation Mechanisms through Molecular Simulation

Abstract

Human islet amyloid polypeptide (hIAPP) is implicated in the onset of type II diabetes and is known to aggregate into amyloid fibrils. However, it is prefibrillar species, not mature fibrils, that are proposed to be cytotoxic. In order to better understand the role of hIAPP aggregation in the onset of disease, as well as to design effective therapeutics, it is crucial to understand the mechanism of early-stage hIAPP aggregation. In this work, we use atomistic molecular dynamics simulations combined with multiple advanced sampling techniques to examine the formation of the hIAPP dimer and trimer. Metadynamics calculations reveal a free energy landscape for hIAPP dimer formation, which suggests multiple possible transition pathways. We employ the finite temperature string method to identify favorable pathways for dimer and trimer formation, along with relevant free energy barriers and intermediate structures. Results provide valuable insights into mechanisms and energetics of hIAPP aggregation.