Department of Chemistry , University of California , Irvine , California 92697 , United States.
Departments of Sociology, Electrical Engineering and Computer Science, and Statistics , University of California , Irvine , California 92697 , United States.
Biochemistry. 2019 Sep 3;58(35):3691-3699. doi: 10.1021/acs.biochem.9b00208. Epub 2019 Aug 19.
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 γD-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 γD-crystallin. At physiologically relevant concentrations, exposed hydrophobic regions in this alternative conformation become primary sites for enhanced interprotein interactions leading to large-scale aggregation.
导致眼睛晶状体晶体蛋白聚集的机制在很大程度上仍然未知。我们使用原子尺度多尺度分子模拟来模拟γD-晶体蛋白及其白内障相关 W42R 变体在无限稀释和生理相关浓度下的溶液构象动力学。我们发现，W42R 变体在溶液中呈现出独特的构象，使天然折叠的希腊键结构域基本保持不变，但缺乏对野生型γD-晶体蛋白稳定性至关重要的疏水结构域界面。在生理相关浓度下，这种替代构象中暴露的疏水区成为增强蛋白质间相互作用的主要部位，导致大规模聚集。
