(638d) Structure, Misfolding and Aggregation of Amylin Protein

Amyloid deposits of amylin in the pancreas are an important characteristic feature encountered in patients with Type-2 diabetes. Amylin aggregates are considered to be important in the disease pathology and have therefore been studied extensively. However, the secondary structures of the individual peptides have not been clearly identified. In this work we present detailed solution structures of rat and human amylin using a combination of Monte Carlo simulations, molecular dynamics simulations, and 2D IR experimental measurements. Results are also presented regarding the early stages of association of such peptides in solution. A method is presented to determine the free energy of distinct bio-molecular conformations. The human amylin protein is found to adopt a secondary structure that exhibits an alpha-helical segment comprising residues 9-17, and a short anti-parallel beta sheet formed between residues 23-27 and 30-34. The folded structure of the human amylin protein is found to be able to misfold into an anti-parallel beta-hairpin, with the turn region comprising of residues 20-23. In contrast, the rat peptide does not exhibit the propensity to form a beta-hairpin. The results of our calculations are consistent with those of our experimental 2D IR measurements. The predicted structure of rat amylin was found also found to be in agreement with previous NMR results. We then examine the process of association of the human peptide using transition path sampling simulations, and we discuss it in the context of the differences in the secondary structure of the rat and human amylin peptides.