Cations bind to the pi face of an aromatic structure through a surprisingly strong, non-covalent force termed the cation-pi 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-pi interactions are important 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.
Cation-interactions in protein structures are identified and evaluated by using an energy-based criterion for selecting significant sidechain pairs. Cation-interactions are found to be common among structures in the Protein Data Bank, and it is clearly demonstrated that, when a cationic sidechain (Lys or Arg) is near an aromatic sidechain (Phe, Tyr, or Trp), the geometry is biased toward one that would experience a favorable cation-interaction. The sidechain of Arg is more likely than that of Lys to be in a cation-interaction. Among the aromatics, a strong bias toward Trp is clear, such that over one-fourth of all tryptophans in the data bank experience an energetically significant cation-interaction.The three-dimensional structure of a protein is determined by a delicate balance of weak interactions. Hydrogen bonds, salt bridges, and the hydrophobic effect all play roles in folding a protein and establishing its final structure. In addition, the cation-interaction (1-3) is increasingly recognized as an important noncovalent binding interaction relevant to structural biology. Theoretical and experimental studies have shown that cation-interactions can be quite strong, both in the gas phase and in aqueous media. A number of studies have established a role for cation-interactions in biological recognition, especially in the binding of acetylcholine (4, 5). Here we present a detailed analysis of the extent and nature of cation-interactions that are intrinsic to a protein's structure and likely contribute to protein stability. We find that energetically significant cation-interactions are common in proteins-a ''typical'' protein will contain several. We also have documented some significant preferences for certain amino acid pairs as partners in a cation-interaction.Important early work indicated a role for cation-interactions in protein structures. Following work by Levitt and Perutz (6-8) suggesting a hydrogen bond between aromatic and amino groups, Burley and Petsko identified the ''amino aromatic'' interaction (9), in which NH-containing groups tend to be positioned near aromatic rings within proteins. It is now appreciated that the interaction of a cationic group with an aromatic-a cation-interaction-is much more favorable than an analogous interaction involving a neutral amine (10, 11). Important subsequent studies by Thornton (12-17) modified the Burley and Petsko analysis, especially with regard to the amino-aromatic ''hydrogen bond.'' In addition, explicit studies of Arg interacting with aromatic residues have been reported by Flocco and Mowbray (18) and by Thornton (14), and other efforts to search the Protein Data Bank (PDB) for cation-interactions between ligands and proteins have been reported (19,20).Previous protein database searches relied on geometric definitions of sidechain interactions, focusing on when a cationic sidechain displayed a certain distance͞angle relationship to an aromatic sidechain. The different geometries of Lys vs. Arg and Trp vs. Phe͞Tyr can make such comparisons proble...
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.
Voltage sensors regulate the conformations of voltage-dependent ion channels and enzymes. Their nearly switch-like response as a function of membrane voltage comes from the movement of positively charged amino acids, arginine or lysine, across the membrane field. We used mutations with natural and unnatural amino acids, electrophysiological recordings and X-ray crystallography to identify a charge transfer center in voltage sensors that facilitates this movement. This center consists of a rigid cyclic 'cap' and two negatively charged amino acids to interact with a positive charge. Specific mutations induce a preference for lysine relative to arginine. By placing lysine at specific locations the voltage sensor can be stabilized in different conformations, thus enabling a dissection of voltage sensor movements and their relationship to ion channel opening.Voltage sensors are membrane proteins that change their conformation in response to voltage differences across the cell membrane. They are best known as components of voltagedependent ion channels, in which voltage sensor conformational changes regulate channel opening. Voltage-dependent K + (Kv) and Na + (Nav) channels produce nerve impulses and voltage-dependent Ca 2+ (Cav) channels initiate muscle contraction and many other cellular processes (1). Certain enzymes also have voltage sensors, which allow the membrane voltage to regulate catalytic activity (2,3).Voltage sensors can exhibit a nearly switch-like dependence on membrane voltage, changing from 'off' to 'on' over a few hundredths of a volt. Such a steep dependence on voltage exists because a large quantity of electric charge -known as gating charge -is transferred across the membrane voltage difference when a sensor switches off to on (4). In the Shaker Kv channel the total gating charge is 12 to 14 elementary charges per channel, or 3.0 to 3.5 elementary charges from each of four voltage sensors (5-7). The charges originate from positive charge carrying amino acids, mostly arginine but occasionally lysine, located on the fourth membranespanning helix (S4) of the voltage sensor (5,6).Crystal structures of voltage sensors from Kv channels show that they consist of only four transmembrane helices surrounded by the lipid membrane (8-11). The seemingly simple structure of the voltage sensor presents an apparent paradox: how does the voltage sensor *To whom correspondence should be addressed. email@example.com. Supporting Online Material Materials and MethodsFigs. S1 to S4 transfer a large quantity of charge across the low dielectric, charge destabilizing interior of the membrane when there are only four helices to 'shield' the charges? Some explanations have posited that the sensor does not physically move its charges very far across the membrane, but rather that it somehow restructures the electric field relative to the charges (12-17). On the other hand, other studies suggest that charged amino acids on S4 move 15 Å to 20 Å across the membrane (18)(19)(20). Such large movements would seem to...
The cation-t interaction is an important, general force for molecular recognition in biological receptors. Through the sidechains of aromatic amino acids, novel binding sites for cationic ligands such as acetylcholine can be constructed. We report here a number of calculations on prototypical cation-7r systems, emphasizing structures of relevance to biological receptors and prototypical heterocycles of the type often of importance in medicinal chemistry. Trends in the data can be rationalized using a relatively simple model that emphasizes the electrostatic component of the cation-ir interaction. In particular, plots of the electrostatic potential surfaces of the relevant aromatics provide useful guidelines for predicting cation-7r interactions in new systems.of relevance to biological receptors and prototype heterocycles of the type often of importance in medicinal chemistry. We find that all the trends in this series are qualitatively reproduced by considering only the electrostatic potential energy surface of the aromatic in the absence of a cation, consistent with the electrostatic model. In addition, the current model successfully rationalizes observations concerning the relative frequency of different aromatic amino acids at biological cation-Ir sites. We also show that the major trends of the ab initio surfaces are reproduced using the much less costly AM1 method, greatly expanding the range of applicability of the method.In recent years, studies of model systems and the analysis of biological macromolecular structures have established the importance of the cation-rr interaction as a force for molecular recognition in aqueous media (1). Appropriately designed cyclophane receptors serve as powerful, general hosts for quaternary ammonium, sulfonium, and guanidinium cations, in large part because of the cation-IT interaction (2-4). In the gas phase, the binding of simple cations to benzene and related structures has been shown to be quite substantial, comparable even to cation-water interactions (5). In addition, a large amount of evidence has now been developed that establishes cation-IT interactions as important in a number of biological binding sites for cations (1,6,7). Cation-IT interactions have been considered in such diverse systems as acetylcholine receptors (nicotinic, muscarinic, and ACh esterase), K+ channels, the cyclase enzymes of steroid biosynthesis, and enzymes that catalyze methylation reactions involving S-adenosylmethionine (1). Cation-Ir interactions have also been invoked to rationalize specific drug-receptor interactions (8)(9)(10)(11)
The nicotinic acetylcholine receptor is the prototype ligand-gated ion channel. A number of aromatic amino acids have been identified as contributing to the agonist binding site, suggesting that cation-interactions may be involved in binding the quaternary ammonium group of the agonist, acetylcholine. Here we show a compelling correlation between: (i) ab initio quantum mechanical predictions of cation-binding abilities and (ii) EC 50 values for acetylcholine at the receptor for a series of tryptophan derivatives that were incorporated into the receptor by using the in vivo nonsense-suppression method for unnatural amino acid incorporation. Such a correlation is seen at one, and only one, of the aromatic residues-tryptophan-149 of the ␣ subunit. This finding indicates that, on binding, the cationic, quaternary ammonium group of acetylcholine makes van der Waals contact with the indole side chain of ␣ tryptophan-149, providing the most precise structural information to date on this receptor. Consistent with this model, a tethered quaternary ammonium group emanating from position ␣149 produces a constitutively active receptor.
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