Influence of the π–π interaction on the hydrogen bonding capacity of stacked DNA/RNA bases

The interplay between aromatic stacking and hydrogen bonding in nucleobases has been investigated via high-level quantum chemical calculations. The experimentally observed stacking arrangement between consecutive bases in DNA and RNA/DNA double helices is shown to enhance their hydrogen bonding ability as opposed to gas phase optimized complexes. This phenomenon results from more repulsive electrostatic interactions as is demonstrated in a model system of cytosine stacked offset-parallel with substituted benzenes. Therefore, the H-bonding capacity of the N3 and O2 atoms of cytosine increases linearly with the electrostatic repulsion between the stacked rings. The local hardness, a density functional theory-based reactivity descriptor, appears to be a key index associated with the molecular electrostatic potential (MEP) minima around H-bond accepting atoms, and is inversely proportional to the electrostatic interaction between stacked molecules. Finally, the MEP minima on surfaces around the bases in experimental structures of DNA and RNA–DNA double helices show that their hydrogen bonding capacity increases when taking more neighboring (intra-strand) stacking partners into account.