Sequence specificity in DNA-drug intercalation: MD simulation and density functional theory approaches.

DNA is an essential target for the treatment of various pathologies, especially cancer. Hence targeting DNA double helix for alteration of its function has been attempted by several ways. Drug-DNA intercalation, one such biophysical process, could not be studied extensively as this requires significant deformation of the receptor DNA. Here we report thorough theoretical investigation of intercalation process in daunomycin-DNA interaction, by performing molecular dynamics simulations of the drug-DNA complexes for various DNA sequences, followed by Free-energy analysis and density functional theory (DFT) based studies to understand the binding preference. The classical energy based analyses indicate that the drug prefers to bind to TC/GA sequence over others. The DFT based energies of supra-molecular complexes are always contaminated with basis set superposition error (BSSE), which can be corrected by counterpoise method. This method is quite effective for systems containing two molecular fragments but is not appropriate for studying interaction between two base pair fragments and the drug intercalated between them. We have adopted an extension of the counterpoise method for BSSE corrected interaction energy calculation. These interaction energies, along with the energy penalty due to un-stacking of the base pairs, also indicate TC/GA sequence is the most preferred sequence for binding.