(362f) Solution State Structures of Human Amylin Peptide (hIAPP) and Its Early Aggregation Process in Solution

The presence of amyloid fibrils of human islet amylin polypeptide (humanamylin) that is produced along with insulin is a common pathological featureof Type II diabetes. A growing body of evidence indicates that the cytotoxic properties of human amylin arise from intermediate structures along the aggregation pathway. A better understanding of aggregation processes could lead to development of therapeutic strategies. In this work, we show that human amylin exists in three distinct conformational states: unstructured, α-helical and β-hairpin. Using advanced molecular simulation methods, including a new thermodynamic integration scheme and Replica Exchange Umbrella Sampling (REUS) methods, we have determined the relative free-energy of such states. In this work, we also present a detailed computational analysis of the folding pathways between states using Transition Path Sampling Monte Carlo simulations (TPS). Misfolding of the human amylin protein begins through formation of contacts near the turn region and proceeds via a zipping mechanism. The increase in β-hairpin size is found to be accompanied by the simultaneous loss of α-helical contacts in the folded state. We also present the transition state involved in the misfolding and identify important variables that form integral components of the reaction coordinate. Furthermore, we analyze the early aggregation process of hIAPP dimmers in solution by identifying all plausible meta-stable states using free energy calculations and multiple state TPS. The early aggregation begins by conversion of both peptides into β-hairpins and formation of contacts between two β-hairpins.