Evidence is presented that molecular recognition through encapsulation processes is largely determined by the volumes of the guest and host. Binding of molecules of suitable dimensions in the internal cavity of a molecular receptor in solution can be expected when the packing coefficient, the ratio of the guest volume to the host volume, is in the range of 0.55 AE 0.09. Larger packing coefficients, up to 0.70, can be reached if the complex is stabilized by strong intermolecular forces such as hydrogen bonds. These considerations also apply to situations in which more than one molecule is encapsulated. Organic liquids are generally characterized by the same packing factors as encapsulation complexes, and it is proposed that the short-range structure of liquids and the complexes resulting from encapsulation are two aspects of the same phenomenon. Similar volume considerations are expected to apply to the binding of substrates in biological receptors.

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)

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Quantitative measures of salt-bridge-type interactions in a highly exposed aqueous environment have been obtained by modifying the well-studied cyclophane platform 1 to include carboxylates in close proximity to bound, cationic guests, producing hosts 2 and 3. Many guests show significantly enhanced binding to 2 and 3, but cations of the RNMe3 + type show little or no enhancement. We propose that the latter observations result from the fact that RNMe3 + compounds have very diffuse positive charges. Guests that show enhanced binding have focused regions of large, positive electrostatic potential. The highly charged 3 is able to bind very polar, very well-solvated guests, including a series of arginine-based dipeptides. Neutral, water-soluble host 4 was prepared and found to show a decreased affinity for cationic guests. We propose a novel induced dipole mechanism to rationalize these results.

We report a systematic evaluation of phenylalanine-to-pentafluorophenylalanine (Phe --> F5-Phe) mutants for the 35-residue chicken villin headpiece subdomain (c-VHP), the hydrophobic core of which features a cluster of three Phe side chains (residues 6, 10, and 17). Phe --> F5-Phe mutations are interesting because aryl-perfluoroaryl interactions of optimal geometry are intrinsically more favorable than aryl-aryl interactions and because perfluoroaryl units are more hydrophobic than are analogous aryl units. One mutant, Phe-10 --> F5-Phe, provides enhanced tertiary structural stability relative to the native sequence. The other six mutants analyzed caused a decrease in stability.