Details

Autor(en) / Beteiligte

• Qi, Ruxi
• Luo, Yin
• Ma, Buyong
• Nussinov, Ruth
• Wei, Guanghong

Titel

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

Ist Teil von

• Biomacromolecules, 2014-01, Vol.15 (1), p.122-131

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 Hα 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.