Molecular Dynamics Simulations Highlight Structural Differences in Similar Intrinsically Disordered Protein Sequences

Amylin, or Islet Amyloid Polypeptide (IAPP), a 37-residue polypeptide produced by beta cells, exists in vivo as an intrinsically disordered protein. The human form, hIAPP, has been implicated in the pathology of Type II Diabetes, where it forms toxic amyloid deposits, while the rat form, rIAPP, is nontoxic. hIAPP has proven to be difficult to study because of its rapid aggregation rate in vitro, so we have utilized molecular dynamics simulation in order to explore the structural properties of the monomer. We have compared the monomeric characteristics of hIAPP and rIAPP as well as two hIAPP mutants, I26P and S20G. Our results lead us to believe that differences in helicity over residues 7-16 may be a key factor influencing aggregation propensity. This is despite the fact that all four of these proteins have identical sequences over said region. Furthermore, we have found that previous studies of micelle-bound structures represent stabilized structures that are transiently sampled by monomers in solution.