Conformational Distribution and α-Helix to β-Sheet Transition of Human Amylin Fragment Dimer

Experiments suggested that the fibrillation of the 11-25 fragment (hIAPP(11-25)) of human islet amyloid polypeptide (hIAPP or amylin) involves the formation of transient alpha-helical intermediates, followed by conversion to beta-sheet-rich structure. However, atomic details of alpha-helical intermediates and the transition mechanism are mostly unknown. We investigated the structural properties of the monomer and dimer in atomistic detail by replica exchange molecular dynamics (REMD) simulations. Transient alpha-helical monomers and dimers were both observed in the REMD trajectories. Our calculated H-alpha chemical shifts based on the monomer REMD run are in agreement with the solution-state NMR experimental observations. Multiple 300 ns MD simulations at 310 K show that alpha-helix-to-beta-sheet transition follows two mechanisms: the first involved direct transition of the random coil part of the helical conformation into antiparallel beta-sheet, and in the second, the alpha-helical conformation unfolded and converted into antiparallel beta-sheet. In both mechanisms, the alpha-helix-to-beta-sheet transition occurred via random coil, and the transition was accompanied by an increase of interpeptide contacts. In addition, our REMD simulations revealed different temperature dependencies of helical and beta-structures. Comparison with experimental data suggests that the propensity for hIAPP(11-25) to form alpha-helices and amyloid structures is concentration- and temperature-dependent.