[Folding@home] Dynamics of an intrinsically disordered protein reveal metastable conformations that potentially seed agg

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J Am Chem Soc. 2013 Oct 30;135(43):16092-101. doi: 10.1021/ja403147m. Epub 2013 Oct 17. ABSTRACT Amyloid fibril deposits of the intrinsically disordered hIAPP peptide are found in 95% of type II diabetes patients, and the aggregation of this peptide is suggested to induce apoptotic cell-death in insulin-producing β-cells. Understanding the structure and dynamics of the hIAPP monomer in solution is thus important for understanding the nucleation of aggregation and the formation of oligomers. In this study, we identify the metastable conformational states of the hIAPP monomer and the dynamics of transitioning between them using Markov state models constructed from extensive molecular dynamics simulations. We show that the overall structure of the hIAPP peptide is random coil-like and lacks a dominant folded...

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