Kang Hongsuk, Yang Zaixing, Zhou Ruhong
Institute of Quantitative Biology, Department of Physics , Zhejiang University , Hangzhou 310027 , China.
Computational Biology Center , IBM Thomas J. Watson Research Center , Yorktown Heights , New York 10598 , United States.
J Am Chem Soc. 2018 Jul 11;140(27):8479-8486. doi: 10.1021/jacs.8b03065. Epub 2018 Jul 2.
Cataracts are a leading cause of vision impairment, which stem from the misfolding and aggregation of crystallins in the eye lens. Despite its prevalence and severity, the detailed mechanism by which misfolded crystallins aggregate into cataracts remains elusive. Recently, in vitro and in vivo experiments demonstrated that lanosterol, a steroid-type compound found in human and animal eyes, can not only prevent cataract formation but also reverse the formation. Inspired by these experimental observations, we investigate the preventive activity of lanosterol in the aggregate formation of human γD-crystallins (HγD-Crys) using all atom molecular dynamics (MD) simulation and free energy perturbation (FEP) techniques. Our results reveal that lanosterol preferentially binds to the HγD-Crys hydrophobic dimerization interface, in particular, to the structured C-terminus (near residues 135-165) with a stronger binding affinity than the unfolded N-terminus. Furthermore, we observe that the C-terminal binding is more favorable than lanosterol self-aggregation, further attesting to lanosterol's efficacy. Finally, we compare the binding free energy of lanosterol with cholesterol using alchemical transformation and discuss the possible correlation of the molecular geometry of steroids with binding affinity.
白内障是视力损害的主要原因，其源于眼晶状体中晶状体蛋白的错误折叠和聚集。尽管白内障普遍存在且严重，但错误折叠的晶状体蛋白聚集成白内障的详细机制仍不清楚。最近，体外和体内实验表明，羊毛甾醇（一种在人和动物眼睛中发现的类固醇类化合物）不仅可以预防白内障的形成，还可以逆转其形成。受这些实验观察结果的启发，我们使用全原子分子动力学（MD）模拟和自由能扰动（FEP）技术研究了羊毛甾醇对人γD-晶状体蛋白（HγD-Crys）聚集形成的预防活性。我们的结果表明，羊毛甾醇优先结合到HγD-Crys的疏水二聚化界面，特别是结合到结构化的C末端（靠近135-165位残基），其结合亲和力比未折叠的N末端更强。此外，我们观察到C末端结合比羊毛甾醇的自聚集更有利，进一步证明了羊毛甾醇的功效。最后，我们使用炼金术转换比较了羊毛甾醇与胆固醇的结合自由能，并讨论了类固醇分子几何形状与结合亲和力之间可能的相关性。
