Effect of Histidine Behaviors on Structural Properties of Human Islet Amyloid Peptides

Abstract

AbstractHistidine behaviors (including tautomeric behaviors and protonation behaviors) have been considered as an origin factor in protein folding and misfolding. However, such effects on human islet amyloid peptide (hIAPP) is still unclear, which are the key points in understanding hIAPP misfolding mechanisms. In current study, to investigate the structural properties of hIAPP peptide with histidine in (δ), (ϵ), and (p) states, three independent replica exchange molecular dynamics simulations were performed. Our results show that β‐sheet structure contents are very low no matter histidine on which state, while high α‐helix contents are obtained in A8‐L16/H18 and G24‐L27/S28 regions. Cluster data suggested that three hIAPP systems are prone to flexible structural features. Further analysis confirmed that the histidine related H‐bonding networks were detected in hIAPP(δ) (N14‐H18) and hIAPP(p) (N14‐H18 and F15‐H18). Moreover, based on overall hIAPP(δ), hIAPP(ϵ), and hIAPP(p) equilibration trajectories, we discovered both sheet and helix structural features in basin of free energy landscape. Our current study contributes to the understanding on conformational changes of hIAPP due to histidine behaviors, which could lead to new insights into histidine behaviors mechanisms.