Effects of the biological backbone on DNA–protein stacking interactions

The π–π stacking (face-to-face) interactions between the five natural DNA or RNA nucleobases and the four aromatic amino acids were compared using three different types of dimers: (1) a truncated nucleoside (nucleobase) stacked with a truncated amino acid; (2) a truncated nucleoside (nucleobase) stacked with an extended amino acid; and (3) a nucleoside (extended nucleobase) stacked with a truncated amino acid. Systematic (MP2/6-31G*(0.25)) potential energy surface scans reveal important information about the effects of the deoxyribose sugar and protein backbone on the structure and binding energy between truncated nucleobase and amino acid models that are typically implemented in the literature. Most notably, electrostatic and steric interactions arising from the bulkiness of the biological backbones can change the preferred relative orientations of DNA and protein π-systems. More importantly, the protein backbone can strengthen the stacking energy (by up to 10 kJ mol−1), while the deoxyribose moiety can strengthen or weaken the stacking interaction depending on the positioning of the amino acid relative to the sugar residue. These effects are likely due to additional interactions between the amino acid or nucleobase ring and the backbone in the extended monomer rather than significant changes in the properties of the biological π-systems upon model extension. Since the present work reveals that all calculated DNA–protein stacking interactions are significant and approach the strength of other noncovalent interactions between biomolecules, both π–π and backbone–π interactions must be considered when attempting to gain a complete picture of DNA–protein binding.