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

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.

Fibrillar dimer formation of islet amyloid polypeptides

“…A large β-strand fraction is also seen for each monomer which corresponds to the β-sheet conformations of hIAPP monomer as described in previous studies. 24,26,27 Large fractions of unassigned structures suggest that the hIAPP dimer can also adopt collapsed and amorphous conformations. Region VII corresponds to the U-shaped conformation that is observed in the mature hIAPP fibril, 17 where the DSSP analysis shows a clear strand-loop-stand feature.…”

“…18,[21][22][23][24][25][26][27][28][29] The full-length hIAPP monomer has been shown, both computationally and experimentally, to adopt various conformations, including unstructured coils, α-helices, long β-hairpins, and mixed α-helical and β-sheet conformations. [23][24][25][26][27][28][30][31][32][33][34] The interconversions among some of these conformations have also been characterized using advanced sampling techniques. 26,27 This complex folding behavior of the hIAPP monomer is also reflected in the multiple conformations observed for the mature fibrils, as discussed above.…”

“…[23][24][25][26][27][28][30][31][32][33][34] The interconversions among some of these conformations have also been characterized using advanced sampling techniques. 26,27 This complex folding behavior of the hIAPP monomer is also reflected in the multiple conformations observed for the mature fibrils, as discussed above.…”

Human IAPP amyloidogenic properties and pancreatic β-cell death

“…Thus, most of the knowledge of the initial phase of hIAPP self-association is based on theoretical methods. Based on a detailed computational analysis, Singh et al [35] reported that in dilute solution, hIAPP can adopt distinct metastable states such as ␣-helical, ␤-hairpin, or unstructured coil, all of them with comparable free energies (Fig. 2).…”

“…It is costored with insulin in the secretory granules from which both are cosecreted through exocytosis in response to ␤-cell secretagogues [20][21][22][23]. The hIAPP/insulin molar ratio in the secretion has been estimated to be 1/100 in healthy individuals and could increase to 1/20 in T2DM [35]. Of note is that in vitro, insulin has an inhibitory effect on hIAPP fibrillogenesis.…”