How do amphiphiles form ion-conducting channels in membranes? Lessons from linear oligoesters

The X-ray crystal structures of biological ion channels are exquisitely complex, but not all natural products capable of forming ion-conducting channels are equally elaborate. Examples such as the peptides gramicidin or alamethicin or the polyene antibiotics amphotericin and nystatin clearly form well-defined channels without requiring a massive protein superstructure. These molecules form the starting point for a supramolecular chemistry challenge: how to create synthetic compounds and systems that catalyze the translocation of ionic species across bilayer membranes mimicking naturally occurring channels. Over the past three decades, supramolecular chemists have developed numerous examples of systems with transport rates and efficiencies that rival natural channels. As the field developed, researchers discovered many compounds that are functional for ion transport but bear very little resemblance to any imagined architectures of ion channels. We and others have followed these lead compounds extensively in a quest to focus on the mechanisms such simple compounds use to achieve their function. These compounds show all the hallmarks of ion channels including high activity, ion specificity, regular time-dependent conductance changes, and in some cases higher-order phenomena such as voltage-dependent activity. In this Account, we summarize experimental evidence derived from an extensive class of oligoester bolaamphiphiles that illustrates how amphiphilic molecules can form ion-conducting channels in membranes. Examination of increasingly simple compounds over the past two decades has shifted the focus away from biological paradigms towards alternative modes for transmembrane ion transport. We have developed new tools to move beyond simple on-off channel openings to complex bursts of high activity. From the perspective of flux, the highly conducting bursts clearly move ions more efficiently than simple on-off openings. High and sustained conductance, whatever its structural origin, has direct applications in amplification of chemical signals or membrane-disrupting biological activity. These results ensure that simple transporters will continue to fascinate and puzzle for a long time to come.