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戈勒姆:自动化和强大的冷电磁导向连接器与显式水分子对接

Zhiyu Zhao¹, Emad Tajkhorshid¹

¹Theoretical and Computational Biophysics Group, NIH Resource Center for Macromolecular Modeling and Visualization, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, and Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, United States.

Journal of chemical information and modeling

|July 11, 2024

概括

GOLEM是一种新的自动化方法,用于在冷电子显微镜 (cryo-EM) 地图中建模小分子. 这种遗传算法准确地预测了连接体的姿势和形状,有助于药物发现.

科学领域:

结构生物学是结构生物学.
计算化学是一种计算化学.
药物发现药物发现

背景情况:

了解联体蛋白相互作用对于合理的药物设计至关重要.
电子显微镜 (cryo-EM) 提供高分辨率的结构数据,但由于的灵活性,难以准确的连接体建模.
在冷电磁图中准确地分配小分子坐标仍然是一个重大挑战.

研究的目的:

开发一种自动化和强大的方法,用于预测在冷电磁图中的连接体姿势和形状.
解决目前在冷-电磁密度内的柔性联结体建模方法的局限性.
为药物发现提供一个工具,以增强冷EM数据的实用性.

主要方法:

开发了GOLEM (实验地图中的干的遗传优化),一种干对接方法.
利用拉马克基因算法进行混合的全球/本地搜索连接体构造,定向和定位空间.
纳入分子能量学和冷-EM地图相关性到得分函数中,包括对水分子的明确考虑.

主要成果:

在冷电磁图中,GOLEM成功地预测了连接体的姿势和形状.
对具有不同分辨率和连接体类型的多个冷EM结构的验证表明与实验密度有很好的一致性.
该方法有效地处理了小分子带的动态和灵活性质.

结论:

GOLEM是一个有效的和自动化的工具,用于在冷EM数据中的联体模拟.
该方法提高了连接物坐标分配的准确性,促进了基于结构的药物设计.
作为免费的VMD插件,GOLEM可供科学界访问,在药物发现中推进冷EM应用.

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