Thermodynamic Description of Polymorphism in Q- and N-Rich Peptide Aggregates Revealed by Atomistic Simulation
Thermodynamic Description of Polymorphism in Q- and N-Rich Peptide Aggregates Revealed by Atomistic Simulation
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DOI：
10.1016/j.bpj.2009.03.062
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发表时间：
2009-07-08
影响因子：
3.4
通讯作者：
Harris, Sarah A.
中科院分区：
文献类型：
--
作者：
Berryman, Joshua T.;Radford, Sheena E.;Harris, Sarah A.
淀粉样原纤维是长的、螺旋对称的蛋白质聚集体，即使在相同的实验条件下生长，其也可以显示出实质性的变化（多态性），包括在β链和原丝水平上的扭曲和结构的改变。这种行为的结构和热力学起源还不清楚。我们进行了分子动力学模拟，以确定肽GNNQQNY的不同多晶型物的热力学性质，基于该肽的淀粉样交叉β晶体的结构，对含有不同数量的原丝的原纤维进行建模。我们还用侧链的新方向以及基于反平行β链的从头设计的结构对原纤维进行了建模。模拟结果表明，这些多晶型物在一定范围的条件下近似等能。结构分析揭示了一个动态重组的静电和氢键的主要和侧链的Gln和Asn残基的特点，这种肽序列。富含Q/N的片段存在于几种淀粉样蛋白和肽中，包括酵母朊病毒Sup 35-N和Ure 2 p，以及人类多Q疾病蛋白，包括共济失调蛋白和亨廷顿蛋白。基于我们的研究结果，我们提出，这些残基灌输一个独特的结构可塑性的淀粉样蛋白纤维，它们包括，合理化的能力，富含这些氨基酸的蛋白质，形成朊病毒菌株的遗传和不同的表型性状。
Amyloid fibrils are long, helically symmetric protein aggregates that can display substantial variation (polymorphism), including alterations in twist and structure at the beta-strand and protofilament levels, even when grown under the same experimental conditions. The structural and thermodynamic origins of this behavior are not yet understood. We performed molecular-dynamics simulations to determine the thermodynamic properties of different polymorphs of the peptide GNNQQNY, modeling fibrils containing different numbers of protofilaments based on the structure of amyloid-like cross-beta crystals of this peptide. We also modeled fibrils with new orientations of the side chains, as well as a de novo designed structure based on anti-parallel beta-strands. The simulations show that these polymorphs are approximately isoenergetic under a range of conditions. Structural analysis reveals a dynamic reorganization of electrostatics and hydrogen bonding in the main and side chains of the Gin and Asn residues that characterize this peptide sequence. Q/N-rich stretches are found in several amyloidogenic proteins and peptides, including the yeast prions Sup35-N and Ure2p, as well as in the human poly-Q disease proteins, including the ataxins and huntingtin. Based on our results, we propose that these residues imbue a unique structural plasticity to the amyloid fibrils that they comprise, rationalizing the ability of proteins enriched in these amino acids to form prion strains with heritable and different phenotypic traits.