The stacking and T-shaped interactions between the natural DNA or RNA nucleobases (adenine, cytosine, guanine, thymine, uracil) and all aromatic amino acids (histidine, phenylalanine, tyrosine, tryptophan) were investigated using ab initio quantum mechanical calculations. We characterized the potential energy surface of nucleobase-amino acid dimers using the MP2/6-31G*(0.25) method. The stabilization energies in dimers with the strongest interactions were further examined at the CCSD(T)/CBS level of theory. Results at the highest level of theory possible for these systems indicate that both stacking and T-shaped interactions are very close in magnitude to biologically relevant hydrogen bonds. Additionally, T-shaped interactions are as strong, if not stronger, than the corresponding stacking interactions. Our systematic consideration of the interaction energies in 485 possible combinations of monomers shows that a variety of these contacts are essential when considering the role of aromatic amino acids in the binding of proteins to DNA or RNA. This work also illustrates how our calculated binding strengths can be used by biochemists to estimate the magnitude of these noncovalent interactions in a variety of DNA/RNA-protein active sites.

The strongest gas-phase MP2/6-31G*(0.25) stacking energies between the aromatic amino acids and the natural or methylated nucleobases were considered. The potential energy surfaces of dimers were searched as a function of the vertical separation, angle of rotation and horizontal displacement between monomers stacked according to their centers of mass. Our calculations reveal that the stacking interactions of adducts for a given nucleobase are dependent on the methylation site (by up to 20 kJ mol(-1)), where the relative magnitudes of the interactions are determined by the dipole moments of the adducts and the proton affinities of nucleobase methylation sites. Nevertheless, the differences in the (gas-phase) stacking of methylated adducts are small compared with the differences between the stacking of the corresponding natural and methylated nucleobases. Indeed, methylation increases the stacking energy by up to 40 kJ mol(-1) (or 135%). Although immersing the dimers in different solvents decreases the gas-phase stacking energies with an increase in the polarity of the environment, base methylation still has a significant effect on the nucleobase stacking ability in solvents with large dipole moments, and, perhaps more importantly, environments that mimic enzyme active sites. Our results shed light on the workings of DNA repairs enzymes that selectively remove a wide variety of alkylated nucleobases over the natural bases.