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bioRxiv · 10.1101/2024.11.20.623795

Automated identification of small molecules in cryo-electron microscopy data with density- and energy-guided evaluation

Muenks, A.·Farrell, D. P.·Zhou, G.·DiMaio, F.
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Abstract

Methodological improvements in cryo-electron microscopy (cryoEM) have made it a useful tool in ligand-bound structure determination for biology and drug design. However, determining the conformation and identity of bound ligands is still challenging at the resolutions typical for cry-oEM. Automated methods can aid in ligand conformational modeling, but current ligand identification tools -- developed for X-ray crystallography data -- perform poorly at resolutions common for cryoEM. Here, we present EMERALD-ID, a method capable of docking and evaluating small molecule conformations for ligand identification. EMERALD-ID identifies 43% of common ligands exactly and identifies closely related ligands in 66% of cases. We then use this tool to discover possible ligand identification errors, as well as previously unidentified ligands. Furthermore, we show EMERALD-ID is capable of identifying ligands from custom ligand libraries of various small molecule types, including human metabolites and drug fragments. Our method provides a valuable addition to cryoEM modeling tools to improve small molecule model accuracy and quality.

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Muenks, A., Farrell, D. P., Zhou, G., DiMaio, F.. 2024-11-20. Automated identification of small molecules in cryo-electron microscopy data with density- and energy-guided evaluation. https://doi.org/10.1101/2024.11.20.623795

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