Lone-pair–π interactions: analysis of the physical origin and biological implications

Lone-pair–π (lp–π) interactions have been suggested to stabilize DNA and protein structures, and to participate in the formation of DNA–protein complexes. To elucidate their physical origin, we have carried out a theoretical multi-approach analysis of two biologically relevant model systems, water–indole and water–uracil complexes, which we compared with the structurally similar chloride–tetracyanobenzene (TCB) complex previously shown to contain a strong charge-transfer (CT) binding component. We demonstrate that the CT component in lp–π interactions between water and indole/uracil is significantly smaller than that stabilizing the Cl−–TCB reference system. The strong lp(Cl−)–π(TCB) orbital interaction is characterized by a small energy gap and an efficient lp–π* overlap. In contrast, in lp–π interactions between water and indole or uracil, the corresponding energy gap is larger and the overlap less efficient. As a result, water–uracil and water–indole interactions are weak forces composed by smaller contributions from all energy components: electrostatics, polarization, dispersion, and charge transfer. In addition, indole exhibits a negative electrostatic potential at its π-face, making lp–π interactions less favorable than O–H⋯π hydrogen bonding. Consequently, some of the water–tryptophan contacts observed in X-ray structures of proteins and previously interpreted as lp–π interactions [Luisi, et al., Proteins, 2004, 57, 1–8], might in fact arise from O–H⋯π hydrogen bonding.