The hydrophobic effect characterises the thermodynamic signature of amyloid fibril growth
The hydrophobic effect characterises the thermodynamic signature of amyloid fibril growth
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DOI：
10.1371/journal.pcbi.1007767
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发表时间：
2020-05-01
影响因子：
4.3
通讯作者：
Abeln, Sanne
中科院分区：
文献类型：
--
作者：
van Gils, Juami Hermine Mariama;van Dijk, Erik;Abeln, Sanne
大多数蛋白质在细胞中折叠成稳定、紧凑的结构。尽管如此，许多蛋白质也有能力粘附在一起，形成长纤维结构，这些结构与包括阿尔茨海默氏症和帕金森氏症在内的多种人类疾病有关。淀粉样蛋白引起粘性的确切性质还不清楚，然而淀粉样蛋白原纤维显示出一些非常特定的热力学特征。有些纤维甚至在低温下不稳定。在这项工作中，我们翻译的疏水性理论，以前用来模拟蛋白质折叠原纤维的形成。我们结合联合收割机这一理论与实验测量，模拟和元数据分析不同类型的原纤维。这使我们能够通过观察温度变化（特别是在低温下）对疏水性的影响来揭示淀粉样蛋白原纤维中粘性的本质。许多蛋白质都有可能聚集成淀粉样蛋白原纤维，这种蛋白质聚合物与多种人类疾病有关，如阿尔茨海默氏症和帕金森氏症。与折叠蛋白质相反，淀粉样蛋白原纤维的热力学稳定性尚未得到很好的理解：熵和疏水性项之间的平衡，包括链熵和疏水效应，特征很差。使用的理论，体外实验，模拟的粗粒度蛋白质模型和元数据分析的组合，我们描绘了占主导地位的淀粉样蛋白原纤维的伸长的双折射和熵的贡献。我们的预测的特征温度依赖性的热签名证实了所进行的量热实验和荟萃分析发表的数据。从这些结果中，我们能够确定必要的条件，以观察冷变性的淀粉样纤维。总的来说，我们表明，淀粉样蛋白原纤维的伸长率与负的热容量，其大小密切相关的疏水表面积，被埋在原纤维形成后，突出的重要性，疏水性原纤维的稳定性。
Author summaryMost proteins fold in the cell into stable, compact structures. Nevertheless, many proteins also have the ability to stick together, forming long fibrillar structures that are associated with a wide range of human disorders including Alzheimer's and Parkinson's disease. The exact nature of the amyloid-causing stickiness is not well understood, nevertheless amyloid fibrils show some very specific thermodynamic characteristics. Some fibrils even destabilise at low temperatures. In this work we translate hydrophobic theory previously used to model protein folding to fibril formation. We combine this theory with experimental measurements, simulations and meta-data analysis of different types of fibrils. This allowed us to unravel the nature of the stickiness in amyloid fibrils by observing the effect of temperature changes, specifically at low temperatures, on hydrophobicity.Many proteins have the potential to aggregate into amyloid fibrils, protein polymers associated with a wide range of human disorders such as Alzheimer's and Parkinson's disease. The thermodynamic stability of amyloid fibrils, in contrast to that of folded proteins, is not well understood: the balance between entropic and enthalpic terms, including the chain entropy and the hydrophobic effect, are poorly characterised. Using a combination of theory, in vitro experiments, simulations of a coarse-grained protein model and meta-data analysis, we delineate the enthalpic and entropic contributions that dominate amyloid fibril elongation. Our prediction of a characteristic temperature-dependent enthalpic signature is confirmed by the performed calorimetric experiments and a meta-analysis over published data. From these results we are able to define the necessary conditions to observe cold denaturation of amyloid fibrils. Overall, we show that amyloid fibril elongation is associated with a negative heat capacity, the magnitude of which correlates closely with the hydrophobic surface area that is buried upon fibril formation, highlighting the importance of hydrophobicity for fibril stability.