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0A73DFF9d01 - E ARTICLES Cation-m Interactions in Chemistry...

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E ARTICLES Cation-m Interactions in Chemistry and Biology: A New View of Benzene, Phe, Tyr, and Trp Dennis A. Dougherty Cations bind to the Tr face of an aromatic structure through a surprisingly strong, non- covalent force termed the cation-Tr interaction. The magnitude and generality of the effect have been established by gas-phase measurements and by studies of model receptors in aqueous media. To first order, the interaction can be considered an electrostatic attraction between a positive charge and the quadrupole moment of the aromatic. A great deal of direct and circumstantial evidence indicates that cation-Tr interactions are im- portant in a variety of proteins that bind cationic ligands or substrates. In this context, the amino acids phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp) can be viewed as polar, yet hydrophobic, residues. Noncovalent intermolecuLlar forces play a major role in determining the structures of biological macromolecules and in mediat- ing processes such as receptor-ligand inter- actions, enzyme-substrate binding, and an- tigen-antibody recognition. Although the hydrophobic effect, hydrogen bonding, and ion pair (salt bridge) interactions have been extensively studied and discussed, there is another important but generally underap- preciated noncovalent binding force. Cat- ions, from simple ions like Li' to more complex organic structures like acetylcho- line (ACh), are strongly attracted to the ar face of benzene and other aromatic struc- tures (Fig. 1). Several features distinguish this cation-IT interaction from other non- covalent binding forces and make it espe- cially well suited to novel types of biological binding. An overview of research efforts from my labs and many other groups is presented here that delineates the scope and impor- tance of cation-IT interactions. Fundamen- tal gas-phase ion studies have led to a model for the physical origin of the effect and suggest a new way of looking at benzene and other aromatic systems. Studies of organic model systems, coupled with a wide range of results from structural biology, have estab- lished the relevance of cation-Tr interac- tions to biological recognition through in- teractions with aromatic side chains from the amino acids Phe, Tyr, and Trp. Most important, not only can a binding site made up of aromatic rings bind cations, it also can compete with the highly favor- able solvation of an ion provided by an aqueous medium. Hence, binding sites can be created that are in one sense polar (in that they are able to bind ions) yet are overall hydrophobic (being composed of hydrocarbon units). This combination of The author is in the Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasade- na, CA 91125, USA. E-mail: [email protected] properties is especially well suited to the interior of a protein or a cell membrane, environments in which cation binding by conventional ion pairing may not be feasi- ble.
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