RNA polymerase and DNA gyrase system setup. The structure of the M. tuberculosis RNA polymerase (PDB:5UH6) , including a 14-base stretch of DNA, 2 RNA nucleotides, 2 zinc ions, a magnesium ion and a bound rifampicin molecule, was solvated with 114,838 waters and 127 sodium ions -the latter to ensure electrical neutrality -creating a cubic simulation unit cell of initial dimensions 20.1 x 15.2 x 13.1 nm. The flexible loop region of each gyrB protein that were not resolved in the structure of the M. tuberculosis DNA gyrase cleavage complex (PDB:5BS8) were modelled in using the ModLoop server . This structure, including the 19-base stretch of DNA, 4 Mg 2+ ions, 2 bound moxifloxacin molecules and 403 crystal waters was placed in a rhombic dodecahedron unit cell with dimensions 13.8 x 13.8 x 9.8 x 0.0 x 0.0 x 0.0 x 0.0 x 6.9 x 6.9 nm. The unit cell was solvated with 59,895 waters, 175 Na + and 112 Cl -ions providing electrical neutrality and a 100mM salt concentration. The generalized AMBER and AMBER ff99SB-idln forcefields were used throughout . To facilitate the covalent bond between gyrA Tyr129 and the phosphate backbone of DNA by GROMACS, two modified amino acids (TYX and TYY) were created. These 'hybrid' amino acids contained the parameters for Tyr, excluding the hydroxyl hydrogen, all nucleotides in the covalently bound DNA chain and the covalent bond between the Tyr hydroxyl oxygen and the corresponding DNA backbone phosphorus atom. The PDB file order and residue naming was adjusted to reflect the modified amino acids. The system was left with a non-integer charge due to the exclusion of the hydrogen atom from Tyr, so a solvent chloride ion was modified to provide a balancing charge.