Cation-p Interactions Involving Aromatic Amino Acids

The cation-p interaction is a general, strong, noncovalent binding force that is used throughout nature. The side chains of the aromatic amino acids [phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp)] provide a surface of negative electrostatic potential than can bind to a wide range of cations through a predominantly electrostatic interaction. In this brief overview, the fundamental nature of the cation-p interaction will be described, relying on fundamental, gas phase studies of the effect. Then, several examples of cation-p interactions involving aromatic amino acids will be described. These include contributions to protein secondary structure, in which Phe/Tyr/Trp lysine (Lys)/arginine interactions are common. We will also describe several examples of protein-ligand interactions that make use of cation-p interactions. We will place special emphasis on the binding of quaternary ammonium ions, such as trimethylated Lys and the neurotransmitter acetylcholine. J. Nutr. 137: 1504S–1508S, 2007. Aromatic amino acids have unique and important properties. Phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp) are generally hydrophobic, but compared with simpler hydrophobic residues, such as leucine or valine, the aromatic amino acids have additional capabilities. Both Tyr and Trp can contribute hydrogen bonds, an important feature. However, there is another reason that aromatic amino acids are substantially overrepresented at protein binding sites and that Trp, in particular, is the most conserved of all amino acids. That is the cation-p interaction, a strong, noncovalent binding interaction that contributes to protein secondary structure and to diverse drug-receptor interactions. Here we present a brief overview of the cation-p interaction. More detailed reviews are available elsewhere. (1–4) We begin with a description of the fundamental nature of the interaction, emphasizing gas phase studies. Then we describe the contribution of cation-p interactions to protein secondary structure and recent examples of cation-p interactions in the binding of ligands to diverse proteins. It is clear from such studies that aromatic amino acids can make special contributions in a number of ways, including the cation-p interaction. Fundamentals of the cation-p interaction Figure 1 summarizes several studies of the cation-p interactions in the gas phase (5–8). Two features of these results are important. First, these are very large binding energies for a clearly noncovalent binding interaction. Importantly, pioneering work by Kebarle in 1981 (6) measured not only the benzene K interaction but also the water K interaction. Everyone would agree that water is a potent ligand for ions, and it is, binding K with a 2DH of 18 kcal/mol. Remarkably, benzene binds the K ion more tightly than water, and this is the first indication that the cation-p interaction is a potentially important binding force. The second feature of Figure 1 is that the results follow a classical electrostatic trend, much as one would see in aqueous solvation energies or crystal lattice energies (5). That is, smaller ions with more focused charges have the larger affinity. These results, and many more, have led us to advocate a primarily electrostatic model for the cation-p interaction (9). While it is certainly true that van der Waals and polarization effects contribute to the cation-p interaction, the defining feature is electrostatic. In fact, most observations concerning the cation-p interaction (and other noncovalent interactions involving simple aromatics) (10) can be rationalized by the following observation: sp carbon is more electronegative than hydrogen. As shown in Figure 2, this creates 6 local C–H bond dipoles around the benzene ring. When summed, these 6 bond dipoles create an overall charge distribution that is a build-up of negative charge in the center of the ring and a belt of positive charge around the edge. 1 Published in a supplement to The Journal of Nutrition. Presented at the ‘‘Conference on Aromatic Amino Acids and Related Substances: Chemistry, Biology, Medicine, and Application’’ held July 20–21, 2006 in Vancouver, Canada. The conference was sponsored by Ajinomoto Company, Inc. The organizing committee for the symposium and Guest Editors for the supplement were: Katsuji Takai, Dennis M. Bier, Luc Cynober, Sidney M. Morris, Jr., and Yoshiharu Shimomura. Guest Editor disclosure: Expenses to travel to the meeting were paid by Ajinomoto Company, Inc. for K. Takai, D. M. Bier, L. Cynober, S. M. Morris, Jr., and Y. Shimomura; D. M. Bier has consulted for Ajinomoto Company, Inc. on scientific issues. 2 Supported by the NIH (NS 34407). 3 Author disclosures: D. A. Dougherty, The Ajinomoto Company, Inc. paid the author’s travel expenses to the TICAAA meeting. 4 Color versions of Figures 4 and 5 are available with the online posting of this paper at jn.nutrition.org. 5 Abbreviations used: ACh, acetylcholine; AChBP, acetylcholine-binding protein; AChE, acetylcholine esterase; Arg, arginine; Cys, cysteine; GABA, g-aminobutyric acid; His, histidine; Lys, lysine; nAChR, nicotinic acetylcholine receptor; Phe, phenylalanine; Trp, tryptophan; Tyr, tyrosine. * To whom correspondence should be addressed. E-mail: dadougherty@caltech.