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)) π-π 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···O, N···H-O, C-H···O) hydrogen bonding and nonconventional (X-H···π (neutral His) or lone-pair···π (protonated His)) contacts. Overall, the effects of discrete His-H(2)O interactions on the neutral histidine-adenine π-π 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 π(+)-π interaction by up to 15 kJ mol(-1) (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 π(+)-π compared with π-π interactions, the π(+)-π binding strengths remain substantially larger than the corresponding π-π contacts. These findings emphasize the distinct nature of π(+)-π and π-π interactions and suggest that π(+)-π contacts can provide significant stabilization in biological systems relative to π-π contacts under many different environmental conditions.