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首页> 外文期刊>The Journal of Chemical Physics >Structural diversity of the soluble trimers of the human amylin(20-29)peptide revealed by molecular dynamics simulations
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Structural diversity of the soluble trimers of the human amylin(20-29)peptide revealed by molecular dynamics simulations

机译：分子动力学模拟揭示人胰岛淀粉样多肽（20-29）可溶性三聚体的结构多样性

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摘要

The human islet amyloid polypeptide (hIAPP) or amylin is a 37-residue hormone found as amyloiddeposits in pancreatic extracts of nearly all type 2 diabetes patients. The fragment 20-29 of sequence SNNFGAILSS (hIAPP20-29) has been shown to be responsible for the amyloidogenicpropensities of the full length protein. Various polymorphic forms of hIAPP20-29 fibrils weredescribed by using Fourier transform infrared (FTIR) and solid-state NMR experiments: unseededhIAPP20-29 fibril with out-of-register antiparallel β-strands, and two forms of seeded hIAPP20-29 fibril, with in-register antiparallel or in-register parallel β-strands. As a first step towardunderstanding this polymorphism, we explore the equilibrium structures of the soluble hIAPP20-29trimer, using multiple molecular dynamics (MD) simulations with the Optimized Potential forEfficient structure Prediction (OPEP) coarse-grained implicit solvent force field for a total length of 3.2 μs. Although, the trimer is found mainly random coil, consistent with the signal measuredexperimentally during the lag phase of hIAPP20-29 fibril formation, the central FGAIL residues have a relative high propensity to form interpeptide /3-sheets and antiparallel β-strands are more probable than parallel β-strands. One MD-predicted out-of-register antiparallel three-strandedβ-sheet matches exactly the FTIR-derived unseeded hIAPP20-29 fibril model. Our simulations, however, do not reveal any evidence of in-register parallel or in-register antiparallel β-sheets as reported for seeded hIAPP20-29 fibrils. All these results indicate that fibril polymorphism ispartially encoded in a trimer.
机译：人胰岛淀粉样蛋白多肽（hIAPP）或淀粉样蛋白是几乎在所有2型糖尿病患者的胰腺提取物中以淀粉样蛋白沉积的形式存在的37个残基激素。已显示序列SNNFGAILSS（hIAPP20-29）的片段20-29负责全长蛋白质的淀粉样蛋白生成倾向。通过使用傅立叶变换红外（FTIR）和固态NMR实验描述了hIAPP20-29原纤维的多种多晶型形式：未接种的反平行β链的非种子hIAPP20-29原纤维，以及两种形式的接种的hIAPP20-29原纤维，配准反平行或配准平行β链。作为了解这种多态性的第一步，我们使用多分子动力学（MD）模拟和优化的有效结构预测（OPEP）粗粒隐式溶剂力场，探索了可溶性hIAPP20-29三聚体的平衡结构，全长3.2微秒尽管发现三聚体主要是无规卷曲，与在hIAPP20-29原纤维形成的滞后阶段实验测得的信号一致，但中央FGAIL残基具有较高的形成肽间/ 3-折叠的倾向，反平行的β链更有可能形成比平行的β链。一个MD预测的套准反平行三链β-折叠完全符合FTIR衍生的非种子hIAPP20-29原纤维模型。然而，我们的模拟并未揭示任何关于种子hIAPP20-29原纤维报道的寄存器内平行或寄存器内反平行β-折叠的证据。所有这些结果表明原纤维多态性在三聚体中部分编码。

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