α-helix to β-hairpin transition of human amylin monomer.

Content Provider	Europe PMC
Author	Singh, Sadanand Chiu, Chi-cheng Reddy, Allam S. de Pablo, Juan J.
Copyright Year	2013
Abstract	The human islet amylin polypeptide is produced along with insulin by pancreatic islets. Under some circumstances, amylin can aggregate to form amyloid fibrils, whose presence in pancreatic cells is a common pathological feature of Type II diabetes. A growing body of evidence indicates that small, early stage aggregates of amylin are cytotoxic. A better understanding of the early stages of the amylin aggregation process and, in particular, of the nucleation events leading to fibril growth could help identify therapeutic strategies. Recent studies have shown that, in dilute solution, human amylin can adopt an α-helical conformation, a β-hairpin conformation, or an unstructured coil conformation. While such states have comparable free energies, the β-hairpin state exhibits a large propensity towards aggregation. In this work, we present a detailed computational analysis of the folding pathways that arise between the various conformational states of human amylin in water. A free energy surface for amylin in explicit water is first constructed by resorting to advanced sampling techniques. Extensive transition path sampling simulations are then employed to identify the preferred folding mechanisms between distinct minima on that surface. Our results reveal that the α-helical conformer of amylin undergoes a transformation into the β-hairpin monomer through one of two mechanisms. In the first, misfolding begins through formation of specific contacts near the turn region, and proceeds via a zipping mechanism. In the second, misfolding occurs through an unstructured coil intermediate. The transition states for these processes are identified. Taken together, the findings presented in this work suggest that the inter-conversion of amylin between an α-helix and a β-hairpin is an activated process and could constitute the nucleation event for fibril growth.
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ISSN	00219606
Volume Number	138
DOI	10.1063/1.4798460
PubMed Central reference number	PMC3643982
Issue Number	15
PubMed reference number	23614446
Journal	The Journal of Chemical Physics [J Chem Phys]
e-ISSN	10897690
Language	English
Publisher	American Institute of Physics
Publisher Date	2013-04-01
Access Restriction	Open
Rights License	Copyright © 2013 American Institute of Physics
Content Type	Text
Resource Type	Article
Subject	Physics and Astronomy Medicine Physical and Theoretical Chemistry