Molecular simulations indicate marked differences in the structure of amylin mutants, correlated with known aggregation propensity.

Human islet amyloid polypeptide (hIAPP), a 37-residue protein cosecreted with insulin by β-cells in the pancreas, is known to form amyloid fibrils in type II diabetes patients. This fibril formation is also associated with β-cell death. However, rat IAPP (rIAPP) does not aggregate into fibrils, nor is it associated with β-cell toxicity. Determining solution properties of hIAPP experimentally is difficult because it aggregates quickly. Our study uses molecular dynamics simulation to explore and compare in-solution characteristics of hIAPP and rIAPP, as well as two single-point hIAPP mutants, hIAPP I26P and hIAPP S20G, which exhibit observed differences from hIAPP in aggregation propensities. We find that all four polypeptide monomers sample structured states in solution. More importantly, differences in the helicity over residues 7-16 may play an important role in early aggregation, although this region is outside of commonly assumed amyloidogenic region 20-29. The long-range contacts, though unexpected of IDPs, cause variation in sampled conformations among four polypeptides within same amino acid sequence. Our results also yield evidence that previously determined structures bound to micelles are also transiently sampled in the solution state. In particular, similarities found in region 8-17 together with the helical differences that we observe in region 7-16 lead us to suggest that the region 7-16 is potentially responsible for amyloidogenic behavior of amylin peptides. Our results also provide support for the proposed mechanism of fibril formation based on experimentally observed transient helices in amyloidogenic peptides.