Facultad de Química, Departamento de Fisicoquímica , Universidad Nacional Autónoma de México , Mexico City 04510 , Mexico.
Center for Arrhythmia Research, Department of Internal Medicine, Division of Cardiovascular Medicine , University of Michigan , Ann Arbor , Michigan 48109 , United States.
J Chem Inf Model. 2020 Feb 24;60(2):777-785. doi: 10.1021/acs.jcim.9b00747. Epub 2019 Dec 4.
Oligomerization and aggregation of γD-crystallins (HγDC) in the eye lens is one of the main causes of cataract development. To date, several congenital mutations related to this protein are known to promote the formation of aggregates. Previous studies have demonstrated that mutations in W42 residue of HγDC lead to the generation of partially unfolded intermediates that are more prone to aggregate. To understand the role of W42 in the stability of HγDC, we performed alchemical free-energy calculations and all-atom molecular dynamics simulations of different W42 mutant models. Our results suggest that substitution of W42 by small size and/or polar residues promotes HγDC denaturation due to the entry of water molecules into the hydrophobic core of the N-terminal domain. Similar behavior was observed in the C-terminal domain of HγDC when mutating the W130 residue located in a homologous position. Moreover, the exposure of the hydrophobic core residues could lead to the formation of aggregation-prone partially unfolded species. Overall, this study takes a step toward understanding the role of HγDC in cataract development.
γD-晶体蛋白（HγDC）的寡聚化和聚集是白内障发展的主要原因之一。迄今为止，已知该蛋白的几种先天性突变可促进聚集物的形成。先前的研究表明，HγDC 中 W42 残基的突变导致部分展开的中间体的产生，这些中间体更容易聚集。为了了解 W42 在 HγDC 稳定性中的作用，我们对不同 W42 突变体模型进行了变分自由能计算和全原子分子动力学模拟。我们的结果表明，由于水分子进入 N 端结构域的疏水区，由小尺寸和/或极性残基取代 W42 会促进 HγDC 变性。当突变位于同源位置的 W130 残基时，HγDC 的 C 端结构域也观察到类似的行为。此外，疏水性核心残基的暴露可能导致形成易于聚集的部分展开的物种。总的来说，这项研究朝着理解 HγDC 在白内障发展中的作用迈出了一步。
