ChemEM: flexible docking of small molecules in Cryo-EM structures using difference maps
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.13.532279v1?rss=1

Authors: Sweeney, A., Mulvaney, T., Topf, M.

Abstract: The rapid advancement of the "resolution revolution" has propelled cryo-electron microscopy (cryo-EM) to the forefront of structure-based drug discovery. However, the majority of cryo-EM structures are solved at medium resolution (3-4A), an unexplored territory for small-molecule docking, due to difficulty in positioning ligands and the surrounding side-chains. Therefore, the development of software capable of reliably and automatically dock ligands into cryo-EM maps at such resolutions is of utmost importance. ChemEM is a novel method that employs cryo-EM data, difference mapping, and a physico-chemical scoring function to flexibly dock one or multiple ligands in a protein binding site. To validate its effectiveness, ChemEM was assessed using a highly curated benchmark containing 33 experimental cryo-EM structures, spanning a resolution range of 2.2-5.6A. In all but one case, the method placed the ligands in the density in an accurate conformation , often better than the PDB deposited solutions. Even without the use of cryo-EM density, the ChemEM scoring function outperformed the well-established docking software AutoDock Vina. Furthermore, the study demonstrates that useful information is present in the map even at low resolutions. ChemEM unlocks the potential of medium-resolution cryo-EM structures for drug discovery.

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