Functionality maps of the ATP binding site of DNA gyrase B: generation of a consensus model of ligand binding

The Multiple Copy Simultaneous Search method (MCSS) was used to construct consensus functionality maps for functional group binding in the ATP binding site of DNA gyrase B. To account for the conformational flexibility of the protein active site, which involves small side chain fluctuations as well as large-scale loop motions, the calculations were done for three different conformations of the 24 kDa subdomain of DNA gyrase B. A postprocessing procedure that employs a continuum dielectric model to include solvent effects was used to calculate the binding free energy for every functional group. These results were ranked according to their affinity for DNA gyrase B and clustered using a new procedure based on van der Waals contacts that is better adapted for cases where multiple conformations are being considered. A total of 23 different functional groups were tested. The results gave consensus maps that indicate those functional group binding sites that are insensitive to the specific protein conformation. The maps also demonstrate that functional groups other than those found in the known ligands may bind competitively in the binding sites of known ligands. This suggests numerous scaffolds that can be used in the development of new ligands for the ATP and coumarinic binding sites in DNA gyrase B. Finally, the calculations show the existence of alternative binding sites near the known binding sites that could be targeted in the rational design for new inhibitors.