A New Protocol for Atomic-Level Protein Structure Modeling and Refinement Using Low-to-Medium Resolution Cryo-EM Density Maps

Zhang Biao; Zhang Xi; Pearce RobinShen Hong-BinZhang Yang

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A New Protocol for Atomic-Level Protein Structure Modeling and Refinement Using Low-to-Medium Resolution Cryo-EM Density Maps

机译：A New Protocol for Atomic-Level Protein Structure Modeling and Refinement Using Low-to-Medium Resolution Cryo-EM Density Maps

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The rapid progress of cryo-electron microscopy (cryo-EM) in structural biology has raised an urgent need for robust methods to create and refine atomic-level structural models using low-resolution EM density maps. We propose a new protocol to create initial models using I-TASSER protein structure prediction, followed by EM density map-based rigid-body structure fitting, flexible fragment adjustment and atomic-level structure refinement simulations. The protocol was tested on a large set of 285 non-homologous proteins and generated structural models with correct folds for 260 proteins, where 28% had RMSDs below 2 angstrom. Compared to other state-of-the-art methods, the major advantage of the proposed pipeline lies in the uniform structure prediction and refinement protocol, as well as the extensive structural re-assembly simulations, which allow for low-to-medium resolution EM density map-guided structure modeling starting from amino acid sequences. Interestingly, the quality of both the image fitting and subsequent structure refinement was found to be strongly correlated with the correctness of the initial I-TASSER models; this is mainly due to the different correlation patterns observed between force field and structural quality for the models with template modeling score (or TM-score, a metric quantifying the similarity of models to the native) above and below a threshold of 0.5. Overall, the results demonstrate a new avenue that is ready to use for large-scale cryo-EM-based structure modeling and atomic-level density map-guided structure refinement. (C) 2020 Elsevier Ltd. All rights reserved.

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《Journal of Molecular Biology》 |2020年第19期|5365-5377|共13页
作者
Zhang Biao; Zhang Xi; Pearce RobinShen Hong-BinZhang Yang;
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作者单位

Shanghai Jiao Tong Univ, Inst Image Proc & Pattern Recognit, Shanghai, Peoples R China;

Univ Michigan, Dept Computat Med & Bioinformat, 100 Washtenaw Ave, Ann Arbor, MI 48109 USA;

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正文语种英语
中图分类分子生物学;
关键词
Cryo-EM; protein structure prediction; structure refinement; structure and density-map fitting; replica-exchange Monte Carlo simulation;

A New Protocol for Atomic-Level Protein Structure Modeling and Refinement Using Low-to-Medium Resolution Cryo-EM Density Maps

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