Hartree-Fock (HF/6-31G*), electron correlation (MP2/6-31G*, B3LYP/6-31G*, B3LYP/6-3IG*(d,p)), and semiempirical (AM1, AM1/SM5.4) calculations were carried out on the DNA AT-specific intercalator tambjamine E in order to investigate the effect of protonation, side chains, electron correlation, and solvent on the inter-ring NCCN rotational barrier and relative planarity of the A and B rings. These properties relate to the flexibility of tambjamine and the ease by which it could adjust its inter-ring twist angle to adopt the propeller twist of DNA in order to form a nonclassical intercalation complex. The E configuration of protonated tambjamine was found to be more stable than the Z due to solvent stabilization and intramolecular hydrogen bonding. Inclusion of electron correlation increased the NCCN rotational barrier by about 2 kcal/mol. Solvent and the presence of the enamine side chain were shown to have a significant effect in lowering the NCCN rotational barrier. For the E configuration of protonated tambjamine, both the Hartree-Fock (HF) and density functional theory (DFT) methods predicted nonplanar minima around 20degrees, whereas DFT calculated the global energy minimum (GEM) to be planar (180degrees) in contrast to the HF nonplanar GEM (166degrees). However, both the HF and DFT results showed that there are broad regions (