Evaluating How Discrete Water Molecules Affect Protein DNA π-π and π+-π Stacking and T-Shaped Interactions: The Case of Histidine-Adenine Dimers

Changes in the magnitude of (M06-2X/6-31+G(d,p)) pi-pi or stacking and T-shaped (nucleobase-edge and amino acid-edge) interactions between (neutral or protonated) histidine (His) and adenine (A) dimers upon microsolvation with up to four discrete water molecules were determined. A variety of histidine water interactions were considered including conventional (N-H center dot center dot center dot O, N center dot center dot center dot H-O, C-H center dot center dot center dot O) hydrogen bonding and nonconventional (X-H center dot center dot center dot pi (neutral His) or lone-pair center dot center dot center dot pi(protonated His)) contacts. Overall, the effects of discrete His-H2O interactions on the neutral histidine adenine pi-pi contacts are negligible (<3 kJ mol(-1) or 15%) regardless of the type of water binding the number of water molecules bound, or the His A dimer (stacked or (amino acid- or nucleobase-edge) T-shaped) configuration. This suggests that previously reported gas-phase binding strengths for a variety of neutral amino acid nucleobase dimers are likely relevant for a wide variety of (microsolvated) environments. In contrast, the presence of water decreases the histidine adenine pi(+)-pi interaction by up to 15 kJ mol (or 30%) for all water binding modes and orientations, as well as different stacked and T-shaped His(+)-A dimers. Regardless of the larger effect of discrete histidine water interactions on the magnitude of the pi-pi compared with pi-pi interactions, the pi(+)-pi a binding strengths remain substantially larger than the corresponding pi-pi contacts.These findings emphasize the distinct nature of pi(+)-pi and pi-pi interactions and suggest that pi(+)-pi contacts can provide significant stabilization in biological systems relative to pi-pi contacts under many different environmental conditions.