A total of 5 snapshots at 1ns each from the molecular dynamics results as obtained from GROMACS, for each of the two drug-DNA complexes was extracted using VMD and that formed the basis of the starting point of the QM/MM calculations. These structures contained the bimolecular system surrounded by water droplets of around 20000-30000 atoms in number and this setup requires a lot of prior work to avoid errors and wrong choices regarding the actual QM/MM calculations. In this chapter, the quantum mechanical/molecular mechanical (QM/MM) calculations were performed using the two-level ONIOM method embedded within the Gaussian 09 program. B3LYP hybrid functional along with 6-31++G basis set was used for the higher layer (QM region of the system) whereas AMBER force field was incorporated for the lower layer (MM region of the system) and all the surrounding water molecules and Na + ions were kept frozen. Figure , shown below, depicts the two layered ONIOM scheme of Gaussian09 used in the current study. The mechanical-embedding version of ONIOM was used for geometry optimization and the energy of the high or QM region is calculated. Now, the co-ordinate of QM region from the optimized system is extracted, which is further subjected to geometry optimization and the energy of QM region in the gas phase is calculated by the same method. The interaction energy between the DNA and drug molecule is calculated with the help of equation: