Conformationally controlled oligocholate membrane transporters: learning through water play

Controlled translocation of molecules and ions across lipid membranes is the basis of numerous biological functions. Because synthetic systems can help researchers understand the more complex biological ones, many chemists have developed synthetic mimics of biological transporters. Both systems need to deal with similar fundamental challenges. In addition to providing mechanistic insights into transport mechanisms, synthetic transporters are useful in a number of applications including separation, sensing, drug delivery, and catalysis. In this Account, we present several classes of membrane transporters constructed in our laboratory from a facially amphiphilic building block, cholic acid. Our "molecular baskets" can selectively shuttle glucose across lipid membranes without transporting smaller sodium ions. We have also built oligocholate foldamers that transiently fold into helices with internal hydrophilic binding pockets to transport polar guests. Lastly, we describe amphiphilic macrocycles, which form transmembrane nanopores in lipid bilayers through the strong associative interactions of encapsulated water molecules. In addition to presenting the different transport properties of these oligocholate transporters, we illustrate how fundamental studies of molecular behavior in solution facilitate the creation of new and useful membrane transporters, despite the large difference between the two environments. We highlight the strong conformational effect of transporters. Because the conformation of a molecule often alters its size and shape, and the distribution of functional groups, conformational control can be used rationally to tune the property of a transporter. Finally, we emphasize that, whenever water is the solvent, its unique properties--small size, strong solvation for ionic functionalities, and an extraordinary cohesive energy density (i.e., total intermolecular interactions per unit volume)--tend to become critical factors to be considered. Purposeful exploitation of these solvent properties may be essential to the success of the supramolecular process involved--this is also the reason for the "learning through water play" in the title of this Account.