MolecularSimulations Indicate Marked Differencesin the Structure of Amylin Mutants, Correlated with Known AggregationPropensity.

Human islet amyloid polypeptide (hIAPP),a 37-residue protein cosecretedwith insulin by β-cells in the pancreas, is known to form amyloidfibrils in type II diabetes patients. This fibril formation is alsoassociated with β-cell death. However, rat IAPP (rIAPP) doesnot aggregate into fibrils, nor is it associated with β-celltoxicity. Determining solutionproperties of hIAPP experimentally is difficult because it aggregatesquickly. Our study uses molecular dynamics simulation to explore andcompare in-solution characteristics of hIAPP and rIAPP, as well astwo single-point hIAPP mutants, hIAPP I26P and hIAPP S20G, which exhibitobserved differences from hIAPP in aggregation propensities. We findthat all four polypeptide monomers sample structured states in solution.More importantly, differences in the helicity over residues 7–16may play an important role in early aggregation, although this regionis outside of commonly assumed amyloidogenic region 20–29.The long-range contacts, though unexpected of IDPs, cause variationin sampled conformations among four polypeptides within same aminoacid sequence. Our results also yield evidence that previously determinedstructures bound to micelles are also transiently sampled in the solutionstate. In particular, similarities found in region 8–17 togetherwith the helical differences that we observe in region 7–16lead us to suggest that the region 7–16 is potentially responsiblefor amyloidogenic behavior of amylin peptides. Our results also providesupport for the proposed mechanism of fibril formation based on experimentallyobserved transient helices in amyloidogenic peptides. [ABSTRACT FROM AUTHOR]