Qi Ruxi, Luo Yin, Ma Buyong, Nussinov Ruth, Wei Guanghong
State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (MOE), and Department of Physics, Fudan University , Shanghai, China.
Biomacromolecules. 2014 Jan 13;15(1):122-31. doi: 10.1021/bm401406e. Epub 2013 Dec 16.
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.
实验表明，人胰岛淀粉样多肽（hIAPP或胰淀素）的11 - 25片段（hIAPP(11 - 25)）的纤维化涉及瞬时α - 螺旋中间体的形成，随后转变为富含β - 折叠的结构。然而，α - 螺旋中间体的原子细节和转变机制大多未知。我们通过副本交换分子动力学（REMD）模拟，详细研究了单体和二聚体的结构特性。在REMD轨迹中观察到了瞬时α - 螺旋单体和二聚体。我们基于单体REMD运行计算的H(α)化学位移与溶液态核磁共振实验观测结果一致。在310 K下进行的多次300 ns分子动力学模拟表明，α - 螺旋到β - 折叠的转变遵循两种机制：第一种涉及螺旋构象的无规卷曲部分直接转变为反平行β - 折叠，第二种是α - 螺旋构象展开并转变为反平行β - 折叠。在这两种机制中，α - 螺旋到β - 折叠的转变都是通过无规卷曲发生的，并且转变伴随着肽间接触的增加。此外，我们的REMD模拟揭示了螺旋结构和β - 结构对温度的不同依赖性。与实验数据的比较表明，hIAPP(11 - 25)形成α - 螺旋和淀粉样结构的倾向与浓度和温度有关。
