Insights into the structural stability and possible aggregation pathways of the LYQLEN peptides derived from human insulin

The LYQLEN peptide from the A chain (residues 13-18) of insulin has been shown to form amyloid-like fibrils. Recently, the structural characterization of this peptide has revealed a general feature of amyloid-like fibers, the so-called “steric zipper”, which is constituted by a tight side-chain complementation of the opposing β-sheet layers. In this study, several molecular dynamics simulations with all-atom explicit water at low pH condition were conducted to investigate the structural stability and aggregation behavior of the LYQLEN peptide of various sizes and its single glycine replacement mutations. Our simulations show that the structural stability of the LYQLEN oligomers increases tremendously with increasing number of β-strands and that the minimal nucleus seed for LYQLEN fibril formation could be as small as a trimer or tetramer. The mutation results also indicate that the hydrophobic interaction between Y2 and E5 plays a crucial role in stabilizing the adjacent β-strands within the same β-sheet layer; while the steric zipper formed via the side chains of L1, Q3, L4, and N6 holds two neighboring β-sheet layers together. Based on the average twist angle between the adjacent β-strands (nearly 9.6°) of the stable LYQLEN oligomers observed in this study, two twist models of the LYQLEN assemblies (SH1-ST60 and SH2-ST60), were built. Finally, two possible aggregation pathways for the LYQLEN peptide were also proposed. Our results provide detailed insights into the stabilization of the LYQLEN oligomers and a thorough understanding of the aggregation pathways of this peptide, which may contribute to imparting further knowledge for designing new or modified capping peptides to inhibit the fibrillization of the LYQLEN peptide and/or insulin.