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 0.97/1.4Å 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. ### Competing Interest Statement The authors have declared no competing interest.

Download data

• Downloaded 605 times
• Download rankings, all-time:
  • Site-wide: 69,476
  • In bioinformatics: 6,765
• Year to date:
  • Site-wide: 50,109
• Since beginning of last month:
  • Site-wide: 42,804

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide