Solution-Binding and Molecular Docking Approaches Combine to Provide an Expanded View of Multidrug Recognition in the MDR Gene Regulator BmrR

Solution-binding and molecular docking have been combined with a diverse collection of chemical probes to further elucidate multidrug (MD) recognition in BmrR. Whereas previous efforts have focused on structural elucidations of MD binding, the present study examines features imparted by structure, including the recognition properties of the ligand-pocket, ligand structural requirements, and key factors that define and influence binding. Whereas MD-pockets are generally believed to be featureless and very hydrophobic, log K_D - clog P correlations observed for BmrR and other polyspecific proteins suggest polar contributions are required for broad-spectrum recognition of amphipathic ligands. We show that molecular docking simulations recapitulate key features of MD recognition and have been employed to further inform contributions from structure. In addition to elaborating our understanding of the structures and functional roles of pocket elements that dictate broad-spectrum binding, molecular docking has implication additional features that likely play major roles, including ligand dynamics and multiple ligand-binding modes.