Lone-Pair-Pi Interactions: Analysis Of The Physical Origin And Biological Implications

Lone-pair-pi (lp-pi) 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-pi interactions between water and indole/uracil is significantly smaller than that stabilizing the Cl--TCB reference system. The strong lp(Cl-)-pi(TCB) orbital interaction is characterized by a small energy gap and an efficient lp-pi(star) overlap. In contrast, in lp-pi 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 pi-face, making lp-pi interactions less favorable than O-H center dot center dot center dot pi hydrogen bonding. Consequently, some of the water-tryptophan contacts observed in X-ray structures of proteins and previously interpreted as lp-pi interactions [Luisi, et al., Proteins, 2004, 57, 1-8], might in fact arise from O-H center dot center dot center dot pi hydrogen bonding.