Structural diversity of the soluble trimers of the human amylin(20–29) peptide revealed by molecular dynamics simulations

Abstract

The human islet amyloid polypeptide (hIAPP) or amylin is a 37-residue hormone found as amyloid deposits in pancreatic extracts of nearly all type 2 diabetes patients. The fragment 20-29 of sequence SNNFGAILSS (hIAPP20-29) has been shown to be responsible for the amyloidogenic propensities of the full length protein. Various polymorphic forms of hIAPP20-29 fibrils were described by using Fourier transform infrared (FTIR) and solid-state NMR experiments: unseeded hIAPP20-29 fibril with out-of-register antiparallel beta-strands, and two forms of seeded hIAPP20-29 fibril, with in-register antiparallel or in-register parallel beta-strands. As a first step toward understanding this polymorphism, we explore the equilibrium structures of the soluble hIAPP20-29 trimer, using multiple molecular dynamics (MD) simulations with the Optimized Potential for Efficient structure Prediction (OPEP) coarse-grained implicit solvent force field for a total length of 3.2 micros. Although, the trimer is found mainly random coil, consistent with the signal measured experimentally during the lag phase of hIAPP20-29 fibril formation, the central FGAIL residues have a relative high propensity to form interpeptide beta-sheets and antiparallel beta-strands are more probable than parallel beta-strands. One MD-predicted out-of-register antiparallel three-stranded beta-sheet matches exactly the FTIR-derived unseeded hIAPP20-29 fibril model. Our simulations, however, do not reveal any evidence of in-register parallel or in-register antiparallel beta-sheets as reported for seeded hIAPP20-29 fibrils. All these results indicate that fibril polymorphism is partially encoded in a trimer.