Join us, on Friday, July 7, 2023, at the American Crystallography Association 2023 Annual Meeting in Baltimore, Maryland for our workshop “Best Practices of Quantum Mechanics Driven Macromolecular Refinement”. This full-day, hands-on, workshop will focus on the application, use, and real-world impact of Quantum Mechanics (QM) and QM/MM (Quantum Mechanics/Molecular Mechanics)-based X-ray and Cryo-EM methods on drug discovery.
About the workshop:
Typically, macromolecular refinement procedures utilize simplistic restraints on bond lengths, angles and so on to ensure the reasonable geometry of the model after the refinement. A significant drawback of using conventional stereochemical-restraints is the lack of the chemical reality observed in the refined model as such intra-molecular restraints, no matter how accurate, do not account for critical atomic, intra- and inter- molecular interactions such as hydrogen bonds, dispersion, electrostatics, polarization, and charge transfer. Instead, each ligand in the structure requires a custom description of the geometry details in the form of Crystallographic Information File (CIF).
Unfortunately, creation of accurate CIF’s is often a nontrivial and error-prone task. One way to overcome those problems and improve the X-ray/Cryo-EM structure quality is to incorporate a quantum mechanics (QM) description of the protein:ligand complex into the refinement procedure. Recent advances in the field (Borbulevych et al, Acta Cryst. 2018, D74,1073) have allowed us to routinely perform QM and mixed-QM/MM-driven refinement on any size protein-ligand system. This level of refinement consistently leads to models with significantly improved ligand and protein:ligand bonded and non-bonded inter- and intra-molecular geometries, improved hydrogen bonding networks (including with bridging waters) and overall improved fit to density. Further, when QM/MM refinement is paired with XModeScore, we can accurately determine tautomer/protomer states, ligand and fragment binding modes, and chirality which directly impacts structure based drug discovery campaigns.
Despite obvious benefits of QM and QM/MM refinement, the use of such advanced techniques is still relatively rare in the crystallographic community. This workshop fits the purpose to educate crystallographers on the theory, benefits, and practical details of conducting the QM/MM driven protein:ligand refinement. Detailed tutorials planned for this workshop aim to lower the barrier for the crystallographic community to use the available QM/MM tools (both locally and in the cloud) in routine refinement of any macromolecular structures.
Workshop space is limited to 50 participants.
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