Dynamics of an intrinsically disordered protein reveal metastable conformations that potentially seed aggregation.

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 structure. Despite this fact, our model reveals a large number of reasonably well-populated metastable conformational states (or local free energy minima) having populations of a few percent or less. The time scales for transitioning between these states range from several microseconds to milliseconds. In contrast to folded proteins, there is no kinetic hub. More strikingly, a few states contain significant amounts of β-hairpin secondary structure and extended hydrophobic surfaces that are exposed to the solvent. We propose that these states may facilitate the nucleation of hIAPP aggregation through a significant component of the conformational selection mechanism, because they may increase their populations upon aggregation by promoting hydrophobic interactions and at the same time provide a flat geometry to seed the ordered β-strand packing of the fibrils.