(706a) Identifying Structural Differences Among Amylin Mutants, Correlated with Aggregation Propensity, Though Molecular Dynamics

Authors: 
Miller, C. M., Lehigh University
Zerze, G. H., Princeton University
Mittal, J., Lehigh University

Human islet amyloid polypeptide (hIAPP) is a 37-residue protein which is cosecreted with insulin by β-cells in the pancreas. It naturally exists as an intrinsically disordered protein (IDP), a class of proteins which lack a stable three-dimensional structure under physiological conditions. However, aggregates of hIAPP have been identified in the pancreas of type II diabetes patients and are associated with β-cell death. Rat amylin, which differs from hIAPP in 6 residues, does not form aggregates and is nontoxic to β-cells.  hIAPP S20G, a naturally occurring mutant, is associated with early-onset type II diabetes and aggregates rapidly in solution, while hIAPP I26P shows both decreased aggregation propensity and inhibitory characteristics to aggregation. Due to rapid aggregation rates of hIAPP in solution, solution structures of hIAPP are difficult to determine experimentally. Molecular dynamics (MD) simulation provides a computational approach to probing IDP structures. MD simulation of hIAPP and rIAPP, along with two hIAPP mutants, indicates all four polypeptides transiently sample structured states in solution. Additionally, structural differences among the polypeptides, specifically increased helicity over residues 7-16, correlates with their aggregation propensity. Furthermore, these results indicate long-range contacts, though unexpected of IDPs, are partly responsible for the structural differences among the four polypeptides. Lastly, simulation of these sequences in solution shows hIAPP naturally samples conformations which have previously been determined in micelle- and protein-bound experiments. In particular, similarities over residues 8-17 provide further support for the significant role of the helical 7-16 region in amyloidogenic behavior of these polypeptides.