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J Phys Chem B. 2018 May 31;122(21):5657-5665. doi: 10.1021/acs.jpcb.7b12083. Epub 2018 Feb 21.

Structural Modulation of Human Amylin Protofilaments by Naturally Occurring Mutations.

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Laboratory of Computational Biology, National Heart, Lung, and Blood Institute , National Institutes of Health , Bethesda , Maryland 20892 , United States.
Department of Chemistry , Yale University , New Haven , Connecticut 06520 , United States.
Institute for Discovery , University College Dublin , Belfield, Dublin 4 , Ireland.
School of Physics , University College Dublin , Dublin 4 , Ireland.


Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37-amino-acid peptide, co-secreted with insulin, and widely found in fibril form in type-2 diabetes patients. By using all-atom molecular dynamics simulations, we study hIAPP fibril segments (i.e., fibrillar oligomers) formed with sequences of naturally occurring variants from cat, rat, and pig, presenting different aggregation propensities. We characterize the effect of mutations on the structural dynamics of solution-formed hIAPP fibril models built from solid-state NMR data. Results from this study are in agreement with experimental observations regarding their respective relative aggregation propensities. We analyze in detail the specific structural characteristics and infer mechanisms that modulate the conformational stability of amylin fibrils. Results provide a platform for further studies and the design of new drugs that could interfere with amylin aggregation and its cytotoxicity. One particular mutation, N31K, has fibril-destabilizing properties, and could potentially improve the solubility of therapeutic amylin analogs.

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