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Automatic and accurate ligand structure determination guided by cryo-electron microscopy maps

Author

Listed:
  • Andrew Muenks

    (University of Washington
    University of Washington)

  • Samantha Zepeda

    (University of Washington)

  • Guangfeng Zhou

    (University of Washington
    University of Washington)

  • David Veesler

    (University of Washington
    University of Washington)

  • Frank DiMaio

    (University of Washington
    University of Washington)

Abstract

Advances in cryo-electron microscopy (cryoEM) and deep-learning guided protein structure prediction have expedited structural studies of protein complexes. However, methods for accurately determining ligand conformations are lacking. In this manuscript, we develop EMERALD, a tool for automatically determining ligand structures guided by medium-resolution cryoEM density. We show this method is robust at predicting ligands along with surrounding side chains in maps as low as 4.5 Å local resolution. Combining this with a measure of placement confidence and running on all protein/ligand structures in the EMDB, we show that 57% of ligands replicate the deposited model, 16% confidently find alternate conformations, 22% have ambiguous density where multiple conformations might be present, and 5% are incorrectly placed. For five cases where our approach finds an alternate conformation with high confidence, high-resolution crystal structures validate our placement. EMERALD and the resulting analysis should prove critical in using cryoEM to solve protein-ligand complexes.

Suggested Citation

  • Andrew Muenks & Samantha Zepeda & Guangfeng Zhou & David Veesler & Frank DiMaio, 2023. "Automatic and accurate ligand structure determination guided by cryo-electron microscopy maps," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36732-5
    DOI: 10.1038/s41467-023-36732-5
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