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Conformational distribution and ?-helix to ?-sheet transition of human amylin fragment dimer.

ABSTRACT: 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 ?-helical intermediates, followed by conversion to ?-sheet-rich structure. However, atomic details of ?-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 ?-helical monomers and dimers were both observed in the REMD trajectories. Our calculated H(?) 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 ?-helix-to-?-sheet transition follows two mechanisms: the first involved direct transition of the random coil part of the helical conformation into antiparallel ?-sheet, and in the second, the ?-helical conformation unfolded and converted into antiparallel ?-sheet. In both mechanisms, the ?-helix-to-?-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 ?-structures. Comparison with experimental data suggests that the propensity for hIAPP(11-25) to form ?-helices and amyloid structures is concentration- and temperature-dependent.

SUBMITTER: Qi R

PROVIDER: S-EPMC6429924 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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