The Effect of Attractive Interactions and Macromolecular Crowding on Crystallins Association.
The Effect of Attractive Interactions and Macromolecular Crowding on Crystallins Association.
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吸引相互作用和大分子拥挤对晶状体蛋白缔合的影响
DOI：
10.1371/journal.pone.0151159
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Song F
中科院分区：
文献类型：
--
作者：
Wei J;Dobnikar J;Curk T;Song F
在生命系统中，蛋白质通常存在于拥挤的环境中，它们的有效相互作用强烈依赖于周围的介质。然而，它们的缔合和解离需要被鲁棒地控制，以实现生物功能。不受控制的蛋白质聚集常常导致疾病。例如，白内障是由透镜蛋白的聚集引起的，即，晶状体蛋白，导致光散射增强和视力受损或失明。为了研究白内障形成的分子起源并设计有效的治疗方法，需要更好地理解大分子拥挤环境中晶状体蛋白的缔合。在这里，我们提出了一个简单的粗粒胶体模型的理论研究，以表征蛋白质的缔合平衡如何依赖于分子间吸引力的大小的一般特征。通过比较分析结果的晶体蛋白溶液中的渗透压的实验数据，我们确定适用于晶体蛋白的有效参数制度。此外，两个模型的组合使我们能够预测晶体蛋白上的结合位点的数量很小，即每个蛋白质一到三个，这与以前的估计不同。我们进一步观察到，拥挤因子是敏感的反应物和拥挤剂之间的大小不对称，蛋白质簇的形状，和小的变化的分子间的吸引力。我们的工作可能会提供一般性的指导方针，如何引导蛋白质的相互作用，以控制他们的协会。
In living systems proteins are typically found in crowded environments where their effective interactions strongly depend on the surrounding medium. Yet, their association and dissociation needs to be robustly controlled in order to enable biological function. Uncontrolled protein aggregation often causes disease. For instance, cataract is caused by the clustering of lens proteins, i.e., crystallins, resulting in enhanced light scattering and impaired vision or blindness. To investigate the molecular origins of cataract formation and to design efficient treatments, a better understanding of crystallin association in macromolecular crowded environment is needed. Here we present a theoretical study of simple coarse grained colloidal models to characterize the general features of how the association equilibrium of proteins depends on the magnitude of intermolecular attraction. By comparing the analytic results to the available experimental data on the osmotic pressure in crystallin solutions, we identify the effective parameters regimes applicable to crystallins. Moreover, the combination of two models allows us to predict that the number of binding sites on crystallin is small, i.e. one to three per protein, which is different from previous estimates. We further observe that the crowding factor is sensitive to the size asymmetry between the reactants and crowding agents, the shape of the protein clusters, and to small variations of intermolecular attraction. Our work may provide general guidelines on how to steer the protein interactions in order to control their association.