The cation-? interaction.

ABSTRACT: The chemistry community now recognizes the cation-? 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-? interaction. Early studies on cyclophanes established that water-soluble, cationic molecules would forego aqueous solvation to enter a hydrophobic cavity if that cavity was lined with ? systems. Important gas phase studies established the fundamental nature of the cation-? interaction. The strength of the cation-? interaction (Li(+) binds to benzene with 38 kcal/mol of binding energy; NH4(+) with 19 kcal/mol) distinguishes it from the weaker polar-? interactions observed in the benzene dimer or water-benzene complexes. In addition to the substantial intrinsic strength of the cation-? interaction in gas phase studies, the cation-? interaction remains energetically significant in aqueous media and under biological conditions. Many studies have shown that cation-? 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-? interaction includes a substantial electrostatic component. The six (four) C(?-)-H(?+) bond dipoles of a molecule like benzene (ethylene) combine to produce a region of negative electrostatic potential on the face of the ? 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-? interactions in protein structures, where lysine or arginine side chains interact with phenylalanine, tyrosine, or tryptophan. In addition, countless studies have established the importance of the cation-? interaction in a range of biological processes. Our work has focused on molecular neurobiology, and we have shown that neurotransmitters generally use a cation-? interaction to bind to their receptors. We have also shown that many drug-receptor interactions involve cation-? interactions. A cation-? 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-? interactions in the recognition of the "histone code," in terpene biosynthesis, in chemical catalysis, and in many other systems.

SUBMITTER: Dougherty DA 

PROVIDER: S-EPMC3957424 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature