Diversity-driven supramolecular and systems chemistry for biological applications

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The Hof research program develops supramolecular binding agents for biological targets in water and other highly competitive solutions. These molecules are unconventional by most views of medicinal and biological chemistry. `Supramolecular binding agents' aren't like drugs or like proteins-they are large, concave, synthetic molecules that describe a binding pocket intended to recognize and bind other molecules. Our program aims to create molecules that will be immediately useful in various applications, and also to uncover fundamental new lessons about how molecules behave in solution. We will create new molecules with new functions that are important in multiple chemical and biological research settings. One set of our applied long-term goals involve creating rapid measurements of biomolecule concentrations and activities (e.g. drug tests, metabolite tests). Nature is salty, and we've learned in recent years how natural salts and other interfering molecules in solution can complicate the creation of successful host molecules. Stimulated by these challenges, we are opening a new track of basic research in which we pursue new fundamental knowledge about the impact of structure, solvent, and solute effects on aqueous molecular recognition. We hope to learn about how natural biomolecular recognition events can tolerate extreme solute concentrations. In the long run, these lessons will feed back into our applied projects, opening avenues for the creation of new salt-tolerant reagents. We are developing new methods on two tracks: molecular diversity and systems chemistry. In the first track, we are introducing new methods to rapidly make and test host molecules for a given property. Some are focused collections of dozens of molecules that explore a novel, biologically compatible (i.e. salt-tolerant) sensing mechanism that we recently invented. Other diversity projects involve new approaches that will allow us to create and test billions of hosts at a time. In the second track, we are inventing ways to create complex adaptive systems made up of dynamic mixtures of host molecules. These have relatively few individual molecules, but they are incredibly complex because they form networks of dynamic connections that change in response to different solution conditions and in response to added analytes. They are designed so the networks can adapt and change themselves in order to achieve a specific task in molecular sensing. In both areas we focus on developing methods that allow rapid synthesis and testing, so that we can quickly identify promising molecules without having to custom-design a host molecule for each and every binding target that might interest us. By taking innovative, method-development approaches, we are creating science that will have a broad impact beyond the individual molecules that we make, and we are also training students who can make their own future impacts in diverse areas of chemical, biology, and biotechnology.