2017 Annual Meeting
(570f) Human Islet Amyloid Polypeptide: Identifying Early-Stage Aggregation Mechanisms through Molecular Simulation
Human islet amyloid polypeptide (hIAPP or human amylin) is implicated in the onset of type II diabetes, which afflicts millions of people worldwide. hIAPP is an amyloidogenic polypeptide which self-assembles into amyloid fibrils. However the prefibrillar species of hIAPP are of particular interest due to their cytotoxic properties. It is essential to investigate the mechanisms of early-stage hIAPP aggregation in order to better understand the role of hIAPP in disease onset, as well as to design effective therapeutics. Using atomistic molecular dynamics simulations with a host of advanced sampling techniques, we reveal mechanistic details of hIAPP dimer and trimer formation. Metadynamics calculations uncover a free energy landscape for the hIAPP dimer, which indicates multiple possible dimerization pathways. We then use finite temperature string method calculations to identify probable pathways for assembling the hIAPP dimer and trimer. We also examine the effects of physiological salt concentration on the aggregation process. Results shed light on the mechanisms and energetics of hIAPP aggregation.