Progressive and accurate assembly of multi-domain protein structures from cryo-EM density maps

Zhou, X.; Li, Y.; Zhang, C.; Zheng, W.; Zhang, G.; Zhang, Y.

doi:10.1101/2020.10.15.340455

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bioRxiv · 10.1101/2020.10.15.340455

Progressive and accurate assembly of multi-domain protein structures from cryo-EM density maps

Zhou, X.·Li, Y.·Zhang, C.·Zheng, W.·Zhang, G.·Zhang, Y.

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Abstract

Progress in cryo-electron microscopy (cryo-EM) has provided the potential for large-size protein structure determination. However, the solution rate for multi-domain proteins remains low due to the difficulty in modeling inter-domain orientations. We developed DEMO-EM, an automatic method to assemble multi-domain structures from cryo-EM maps through a progressive structural refinement procedure combining rigid-body domain fitting and flexible assembly simulations with deep neural network inter-domain distance profiles. The method was tested on a large-scale benchmark set of proteins containing up to twelve continuous and discontinuous domains with medium-to-low-resolution density maps, where DEMO-EM produced models with correct inter-domain orientations (TM-score >0.5) for 98% of cases and significantly outperformed the state-of-the-art methods. DEMO-EM was applied to SARS-Cov-2 coronavirus genome and generated models with average TM-score/RMSD of 0.97/1.4[A] to the deposited structures. These results demonstrated an efficient pipeline that enables automated and reliable large-scale multi-domain protein structure modeling with atomic-level accuracy from cryo-EM maps.

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Zhou, X., Li, Y., Zhang, C., Zheng, W., Zhang, G., Zhang, Y.. 2020-10-16. Progressive and accurate assembly of multi-domain protein structures from cryo-EM density maps. https://doi.org/10.1101/2020.10.15.340455

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