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首页> 外文期刊>Journal of Molecular Biology >Building and refining protein models within cryo-electron microscopy density maps based on homology modeling and multiscale structure refinement.
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Building and refining protein models within cryo-electron microscopy density maps based on homology modeling and multiscale structure refinement.

机译：基于同源性建模和多尺度结构优化，在冷冻电子显微镜密度图中建立和完善蛋白质模型。

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Automatic modeling methods using cryoelectron microscopy (cryoEM) density maps as constraints are promising approaches to building atomic models of individual proteins or protein domains. However, their application to large macromolecular assemblies has not been possible largely due to computational limitations inherent to such unsupervised methods. Here we describe a new method, EM-IMO (electron microscopy-iterative modular optimization), for building, modifying and refining local structures of protein models using cryoEM maps as a constraint. As a supervised refinement method, EM-IMO allows users to specify parameters derived from inspections so as to guide, and as a consequence, significantly speed up the refinement. An EM-IMO-based refinement protocol is first benchmarked on a data set of 50 homology models using simulated density maps. A multiscale refinement strategy that combines EM-IMO-based and molecular dynamics-based refinement is then applied to build backbone models for the seven conformers of the five capsid proteins in our near-atomic-resolution cryoEM map of the grass carp reovirus virion, a member of the Aquareovirus genus of the Reoviridae family. The refined models allow us to reconstruct a backbone model of the entire grass carp reovirus capsid and provide valuable functional insights that are described in the accompanying publication [Cheng, L., Zhu, J., Hui, W. H., Zhang, X., Honig, B., Fang, Q. & Zhou, Z. H. (2010). Backbone model of an aquareovirus virion by cryo-electron microscopy and bioinformatics. J. Mol. Biol. (this issue). doi:10.1016/j.jmb.2009.12.027.]. Our study demonstrates that the integrated use of homology modeling and a multiscale refinement protocol that combines supervised and automated structure refinement offers a practical strategy for building atomic models based on medium- to high-resolution cryoEM density maps.
机译：使用低温电子显微镜（cryoEM）密度图作为约束条件的自动建模方法是建立单个蛋白质或蛋白质域原子模型的有前途的方法。但是，由于这种无监督方法固有的计算局限性，将它们应用于大型大分子组装件的可能性很大。在这里，我们描述了一种新方法，EM-IMO（电子显微镜迭代模块化优化），用于使用cryoEM映射作为约束条件来构建，修改和完善蛋白质模型的局部结构。作为一种监督改进方法，EM-IMO允许用户指定从检查得出的参数，以便进行指导，从而显着加快改进速度。首先使用模拟的密度图在基于50个同源性模型的数据集上对基于EM-IMO的优化协议进行基准测试。然后，将结合基于EM-IMO和基于分子动力学的精细化方法的多尺度改进策略应用于草鱼呼肠孤病毒病毒颗粒的近原子分辨率cryoEM图中，为五个衣壳蛋白的七个构象体建立骨架模型。呼肠孤病毒科的水痘病毒属的成员。完善的模型使我们能够重建整个草鱼呼肠孤病毒衣壳的骨架模型，并提供有价值的功能见解，这些见解在随附的出版物中[Cheng，L.，Zhu，J.，Hui，WH，Zhang，X.，Honig ，B.，Fang，Q.＆Zhou，ZH（2010）。通过冷冻电子显微镜和生物信息学对水痘病毒粒子的骨干模型。 J.摩尔生物学（这个问题）。 doi：10.1016 / j.jmb.2009.12.027。]。我们的研究表明，将同源性建模和结合监督和自动结构细化的多尺度细化协议相结合，为基于中至高分辨率cryoEM密度图构建原子模型提供了实用的策略。

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