A Molecular Orbital Study of Tambjamine E and Analogues
journal contributionposted on 20.05.2004, 00:00 by William J. Skawinski, Thomas J. Venanzi, Carol A. Venanzi
Hartree−Fock (HF/6-31G*), electron correlation (MP2/6-31G*, B3LYP/6-31G*, B3LYP/6-31G*(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 20°, whereas DFT calculated the global energy minimum (GEM) to be planar (180°) in contrast to the HF nonplanar GEM (166°). However, both the HF and DFT results showed that there are broad regions (∠NCCN = 0−30° and 150−180°) in which there is a minimal energetic cost for the E configuration of protonated tambjamine to adopt a nonplanar conformation. Such flexibility of tambjamine around the inter-ring bond could allow the molecule to adjust its NCCN angle to fit the propeller twist of the DNA base pair in order to form a nonclassical intercalation complex.