(588b) Effects of Structural Differences in Amylin Sequences on Their Aggregation Propensity
Aggregation of normally soluble proteins to form insoluble amyloid fibers characterizes amyloidosis. These deposits forming a cross-beta structure affect normal tissue function and are associated with pathology in more than 20 diseases including Alzheimer’s, Parkinson’s, and type II diabetes. One such protein, Human Islet Amyloid Polypeptide (hIAPP) or human amylin which is a 37-amino acid peptide has been found to form amyloid fibrils in the pancreas of type II diabetes patients. However, rat IAPP (rIAPP), which differs from hIAPP by six residues, is known not to form amyloid fibrils, whereas a naturally-occurring point mutant of hIAPP (S20G) is known to form amyloid more quickly and be linked with early onset of type II diabetes. On the other hand, another point mutation of hIAPP (I26P) was reported to resist and potentially inhibit aggregation of the wild-type hIAPP. Here, we have studied various full-length IAPP monomers in solution by replica exchange molecular dynamics simulation and an optimized fully atomistic protein force field, Amber03w. We find that alpha-helix propensity in region spanning residues 7 to 16 correlates very well with the known aggregation propensity of these amylin sequences. The peptides with higher alpha-helix stability in this region aggregate more rapidly. We further found that the secondary structure adopted in solution by hIAPP is strikingly similar to the NMR structures in presence of micelles. We will discuss the implications of the above observations in early oligomerization and aggregation mechanisms.