title: Conformational distribution and α-helix to β-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 α-helical intermediates, followed by conversion to β-sheet-rich structure. However, atomic details of α-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 α-helical monomers and dimers were both observed in the REMD trajectories. Our calculated H(α) 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 α-helix-to-β-sheet transition follows two mechanisms: the first involved direct transition of the random coil part of the helical conformation into antiparallel β-sheet, and in the second, the α-helical conformation unfolded and converted into antiparallel β-sheet. In both mechanisms, the α-helix-to-β-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 β-structures. Comparison with experimental data suggests that the propensity for hIAPP(11-25) to form α-helices and amyloid structures is concentration- and temperature-dependent.
authors: State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (MOE), and Department of Physics, Fudan University , Shanghai, China.
authors: Ruxi
authors: R
authors: Qi
authors: Yin
authors: Y
authors: Luo
authors: Buyong
authors: B
authors: Ma
authors: Ruth
authors: R
authors: Nussinov
authors: Guanghong
authors: G
authors: Wei
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011487:Protein Conformation; D055503:Protein Multimerization / Q000502:physiology*; D017433:Protein Structure, Secondary
chemical_list: D058228:Islet Amyloid Polypeptide