Striving to understand the properties of universal nucleobases: A computational study of azole carboxamides

Density functional theory (DFT) is used to study the properties of a series of azole carboxamides in attempts to better understand why these molecules do not have an equal affinity for all natural DNA (RNA) nucleobases, which is an important criterion for universal bases. The thermodynamics and kinetics for bond rotations that afford four azole carboxamide conformers, which each bind to a different natural (DNA) base, are studied. It is concluded that a particular conformer of some azole carboxamides is favorably stabilized; therefore, these molecules will likely preferentially bind to a particular natural base. The geometries and binding energies are calculated for complexes formed between azole carboxamides and natural bases. Our calculations indicate that some complexes are highly distorted and therefore likely reduce the stability of duplexes. Our calculations also indicate that azole carboxamides bind to natural bases with varying affinities. Furthermore, the azole carboxamide binding interactions are generally significantly less than those in the corresponding natural base pair, with the exception of the thymine (or uracil) azole carboxamide complexes. Our calculations provide insight into interactions between azole carboxamides and the natural bases and allow suggestions to be made regarding why these compounds do not function as universal nucleobases.