Title: 3128-Pos, BoardB558: Accurate determination of tautomeric/protonation states in Quantum-Mechanic (QM) driven macromolecular crystallographic refinement
Presenter: Oleg Y. Borbulevych and Lance M. Westerhoff
Location: Baltimore Convention Center, Baltimore, MD
Download: Available after conference
Structure Based Drug Discovery (SBDD) is employed by virtually all pharmaceutical research and development organizations. Gaining an understanding of the protein:ligand complex structure along with the proper protonation and explicit solvent effects is crucial for obtaining meaningful results from docking, thermodynamic calculations, active site exploration, and ultimately lead optimization. Recently, we incorporated our linear-scaling, quantum mechanics (QM) DivCon tool with Phenix (e.g. Phenix/DivCon) in order to accurately elucidate the protein:ligand complex molecular structure. An intrinsic problem of the X-ray crystallographic data is its inability to detect hydrogen atoms – even at higher resolutions. Hence, it is generally extremely difficult to experimentally determine the protonation/tautomeric state of the ligand and the surrounding active site. Traditionally, protonation can be established using the neutron diffraction; however, experimental requirements such as reliance on very large crystals and on deuterium exchange limit the method’s suitability in SBDD. In order to address this X-day data deficiency, we have challenged Phenix/DivCon with various protonation candidates and applied rigorous statistical analyses to measure the agreement between the 3D structure of each candidate with electron density. While through the experiment we still cannot directly observe hydrogen atoms, using the accurate QM functional we are able to observe the presence/absence of hydrogen atoms by studying their influences on bound heavy atoms (Carbon, Nitrogen, Oxygen).