Simulation-Based Methods for Model Building and Refinement in Cryoelectron Microscopy.,Journal of Chemical Information and Modeling

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Simulation-Based Methods for Model Building and Refinement in Cryoelectron Microscopy.
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2020-03-23 , DOI: 10.1021/acs.jcim.0c00087
Thomas Dodd _{1,

2} , Chunli Yan _{1,

2} , Ivaylo Ivanov _{1,

2}

Affiliation

Advances in cryoelectron microscopy (cryo-EM) have revolutionized the structural investigation of large macromolecular assemblies. In this review, we first provide a broad overview of modeling methods used for flexible fitting of molecular models into cryo-EM density maps. We give special attention to approaches rooted in molecular simulations—atomistic molecular dynamics and Monte Carlo. Concise descriptions of the methods are given along with discussion of their advantages, limitations, and most popular alternatives. We also describe recent extensions of the widely used molecular dynamics flexible fitting (MDFF) method and discuss how different model-building techniques could be incorporated into new hybrid modeling schemes and simulation workflows. Finally, we provide two illustrative examples of model-building and refinement strategies employing MDFF, cascade MDFF, and RosettaCM. These examples come from recent cryo-EM studies that elucidated transcription preinitiation complexes and shed light on the functional roles of these assemblies in gene expression and gene regulation.

中文翻译：

电子仿真中基于仿真的模型建立和优化方法。

低温电子显微镜（cryo-EM）的进步彻底颠覆了大分子组装体的结构研究。在这篇综述中，我们首先提供用于将分子模型灵活地拟合到低温EM密度图中的建模方法的广泛概述。我们特别关注植根于分子模拟的方法-原子分子动力学和蒙特卡洛。给出了方法的简要说明，并讨论了它们的优点，局限性和最流行的替代方法。我们还描述了广泛使用的分子动力学灵活拟合（MDFF）方法的最新扩展，并讨论了如何将不同的模型构建技术结合到新的混合建模方案和仿真工作流程中。最后，我们提供了两个使用MDFF，级联MDFF和RosettaCM进行模型构建和优化策略的示例。这些例子来自最近的cryo-EM研究，该研究阐明了转录预启动复合物，并阐明了这些装配在基因表达和基因调控中的功能。

更新日期：2020-03-23

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