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bioRxiv · 10.1101/2022.08.16.504149

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

Muenks, A.·Zepeda, S.·Zhou, G.·Veesler, D.·DiMaio, F.
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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 a tool for automatically determining ligand structures guided by medium-resolution cryoEM density. We show this method is robust at predicting ligands in maps as low as 6[A] resolution, and is able to correct receptor sidechain errors. Combining this with a measure of placement confidence, and running on all protein/ligand structures in EMDB, we show that 58% of ligands replicate the deposited model, 16% confidently find alternate conformations, 22% have ambiguous density where multiple conformations might be present, and 4% are incorrectly placed. For five cases where our approach finds an alternate conformation with high confidence, high-resolution crystal structures validate our placement. This tool and the resulting analysis should prove critical in using cryoEM to investigate protein-ligand complexes.

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Muenks, A., Zepeda, S., Zhou, G., Veesler, D., DiMaio, F.. 2022-08-17. Automatic and accurate ligand structure determination guided by cryo-electron microscopy maps. https://doi.org/10.1101/2022.08.16.504149

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