Building accurate atomic models of receptor-ligand complexes in cryo-EM Coulomb potential maps is often a challenging task as the resolution is often too low to create an unambiguous pose. To this end, we developed two computational tools: we implemented our advanced OPLS3e/VSGB force field and implicit solvent model as a restraint model in the popular PHENIX real space refine tool; and we created a variation of Glide Small Molecule Docking that includes a real-space cross-correlation term, to allow the identification of a set of possible ligand conformations that are consistent with the EM data. We validated our tools individually by re-refining and re-docking deposited cryo-EM based receptor-ligand complexes, showing similar and higher quality structure and poses, respectively, based on energy calculations, correlation values and MolProbity metrics. Finally, we show how these tools were used as part of a cryo-EM enabled structure-based drug discovery effort to design class A streptogramin antibiotics with improved resistance profiles.

Robust modeling of receptor-ligand complexes in cryo-EM maps by combining glide docking and force field based refinement for cryo-EM enabled drug design of class A streptogramin antibiotics

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.