The Cation-π Interaction

By D. Dougherty. Accounts of Chemical Research, 2012

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CONSPECTUS The chemistry community now recognizes the cation-π interaction as a major force for molecular recognition, joining the hydrophobic effect, the hydrogen bond, and the ion pair in determining macromolecular structure and drug-receptor interactions. This Account provides the author’s perspective on the intellectual origins and fundamental nature of the cation-π interaction. Early studies on cyclophanes established that water-soluble, cationic molecules would forgo aqueous solvation to enter a hydrophobic cavity if that cavity was lined with π systems. Important gas phase studies established the fundamental nature of the cation-π interaction. The strength of the cation-π interaction – Li+ binds to benzene with 38 kcal/mol of binding energy; NH4+ with 19 kcal/mol– distinguishes it from the weaker polar-π interactions observed in the benzene dimer or water-benzene complexes. In addition to the substantial intrinsic strength of the cation-π interaction in gas phase studies, the cation-π interaction remains energetically significant in aqueous media and under biological conditions. Many studies have shown that cation-π interactions can enhance binding energies by 2 – 5 kcal/mol, making them competitive with hydrogen bonds and ion pairs in drug-receptor and protein-protein interactions. As with other noncovalent interactions involving aromatic systems, the cation-π interaction includes a substantial electrostatic component. The six (four) Cδ−–Hδ+ bond dipoles of a molecule like benzene (ethylene) combine to produce a region of negative electrostatic potential on the face of the π system. Simple electrostatics facilitate a natural attraction of cations to the surface. The trend for (gas phase) binding energies is Li+>Na+>K+>Rb+: as the ion gets larger the charge is dispersed over a larger sphere and binding interactions weaken, a classical electrostatic effect. On other hand, polarizability does not define these interactions. Cyclohexane is more polarizable than benzene, but a decidedly poorer cation binder. Many studies have documented cation-π interactions in protein structures, where Lys or Arg side chains interact with Phe, Tyr, or Trp. In addition, countless studies have established the importance of cation-π interaction in a range of biological processes. Our work has focused on molecular neurobiology, and we have shown that neurotransmitters generally use a cation-π interaction to bind to their receptors. We have also shown that many drug-receptor interactions involve cation-π interactions. A cation-π interaction plays a critical role in the binding of nicotine to ACh receptors in the brain, an especially significant case. Other researchers have established important cation-π interactions in the recognition of the “histone code,” in terpene biosynthesis, in chemical catalysis, and in many other systems.

Subfields: Molecular Biology, Physical and Theoretical Chemistry, Spectroscopy

View Paper: https://www.semanticscholar.org/paper/69a1497585a2bad16153697484ba6a5d3ba20936

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