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首页> 外文期刊>Biochemistry >Molecular Mechanism of Aggregation of the Cataract-Related gamma D-Crystallin W42R Variant from Multiscale Atomistic Simulations
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Molecular Mechanism of Aggregation of the Cataract-Related gamma D-Crystallin W42R Variant from Multiscale Atomistic Simulations

机译:多尺度原子模拟的白内障相关γD晶体W42R变体聚集的分子机制

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摘要

The mechanisms leading to aggregation of the crystallin proteins of the eye lens remain largely unknown. We use atomistic multiscale molecular simulations to model the solution-state conformational dynamics of gamma D-crystallin and its cataract-related W42R variant at both infinite dilution and physiologically relevant concentrations. We find that the W42R variant assumes a distinct conformation in solution that leaves the Greek key domains of the native fold largely unaltered but lacks the hydrophobic interdomain interface that is key to the stability of wild-type gamma D-crystallin. At physiologically relevant concentrations, exposed hydrophobic regions in this alternative conformation become primary sites for enhanced interprotein interactions leading to large-scale aggregation.
机译:导致眼镜晶体晶体聚集的机制仍然很大程度上是未知的。 我们使用原子多尺度分子模拟来模拟γD-结晶素的溶液状态构象动态及其白内障相关的W42R变体,无限稀释和生理学相关浓度。 我们发现W42R变型在溶液中呈现不同的构象,使得天然折叠的希腊密钥结构域在很大程度上不置换但缺乏疏水性互联界面,这是野生型γD-晶体稳定性的关键。 在生理学上相关的浓度下,在这种替代构象中暴露的疏水区成为导致大规模聚集的增强诠释的主要部位。

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