Molecular Insights into the Role of Water in Early-stage Human Amylin Aggregation

Abstract

Human islet amyloid polypeptide (hIAPP or human amylin) is known to aggregate into amyloid fibrils and is implicated in the development of type II diabetes. Prefibrillar species in particular have been linked to cell loss, prompting detailed investigation of early-stage hIAPP aggregation. Insights into the mechanisms underlying early-stage aggregation and the key intermediate structures formed during aggregation are valuable in understanding disease onset at the molecular level and guiding design of effective therapeutic strategies. Here, we use atomistic molecular dynamics simulations with the finite temperature string method to identify and compare multiple pathways for hIAPP trimer formation in water. We focus on the comparison between trimerization from three disordered hIAPP chains (which we call “3-chain assembly”) and trimerization from an hIAPP dimer approached by a single disordered chain (called “2+1 assembly”). We show that trimerization is a process uphill in free energy, regardless of the trimerization mechanism, and that a high free energy barrier of 40 kBT must be crossed in 2+1 assembly compared to a moderate barrier of 12 kBT for 3-chain assembly. We find this discrepancy to originate from differences in molecular-level water interactions involved in the two trimerization scenarios. Furthermore, we find that the more thermodynamically favorable 3-chain assembly begins from a previously identified dimer intermediate exhibiting transient β-sheet character, which is then incorporated into a similar trimer intermediate, suggesting stepwise aggregation dynamics.