Improving sampling of crystallographic disorder in ensemble refinement.
Improving sampling of crystallographic disorder in ensemble refinement.
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DOI：
10.1107/s2059798321010044
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发表时间：
2021-11-01
期刊：
影响因子：
--
通讯作者：
Pearce NM
中科院分区：
文献类型：
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作者：
Ploscariu N;Burnley T;Gros P;Pearce NM
改进的合奏细化方法的描述和证明。这些改进导致更多的物理意义和可解释的大分子系综。包合细化，分子动力学的结晶细化的应用，明确建模的大分子结构中固有的无序。这些集成模型已被证明比传统的单模型结构产生更准确的结构。然而，次优采样的分子动力学模拟和建模的晶体学无序的方法的效用有限，并可能导致非物理和应变模型。在这里，两个改进的合奏内实施凤凰细化方法：DEN约束，引导局部采样的构象，并允许更强大的探索局部构象景观，和埃赫特无序模型，允许选择更有物理意义和有效的无序模型参数化的连续无序成分内的晶体。这些改进导致晶体中大分子的模拟更加一致和物理上可解释，并允许在不同尺度上系统地探索结构异质性和无序。新的方法证明了几个案例研究和SARS-CoV-2的主要蛋白酶，并演示了如何选择的障碍模型影响的类型的障碍，是由受约束的分子动力学模拟采样。
Improvements to the ensemble refinement method are described and demonstrated. These improvements lead to more physically meaningful and interpretable macromolecular ensembles. Ensemble refinement, the application of molecular dynamics to crystallographic refinement, explicitly models the disorder inherent in macromolecular structures. These ensemble models have been shown to produce more accurate structures than traditional single-model structures. However, suboptimal sampling of the molecular-dynamics simulation and modelling of crystallographic disorder has limited the utility of the method, and can lead to unphysical and strained models. Here, two improvements to the ensemble refinement method implemented within Phenix are presented: DEN restraints, which guide the local sampling of conformations and allow a more robust exploration of local conformational landscapes, and ECHT disorder models, which allow the selection of more physically meaningful and effective disorder models for parameterizing the continuous disorder components within a crystal. These improvements lead to more consistent and physically interpretable simulations of macromolecules in crystals, and allow structural heterogeneity and disorder to be systematically explored on different scales. The new approach is demonstrated on several case studies and the SARS-CoV-2 main protease, and demonstrates how the choice of disorder model affects the type of disorder that is sampled by the restrained molecular-dynamics simulation.