We work primarily in the field of supramolecular chemistry, which is concerned with the interactions between molecules. These intermolecular interactions are driven by physical forces such as ionic interactions, dipole-dipole interactions, van der Waals forces, and the hydrophobic effect. Intermolecular interactions are fundamental to biochemistry and are required to form functional biological structures, such as proteins and nucleic acids, ribosomes, viral capsids, cell membranes, and organelles. Most processes in biology also require the cooperation between molecules, which involves their selective, noncovalent interaction. The molecular partners “recognize” one another because they have complementary shapes and polarities, allowing them to fit together and stick tightly.
Supramolecular chemists have long sought to mimic the molecular recognition that occurs in biological systems in order to develop principles by which we can design synthetic molecules to recognize biological molecules and to construct new, functional entities of matter. Drugs are an excellent example; they are typically small organic molecules that bind to proteins in order to block their natural functions. The Urbach group is interested in organic molecules that bind to proteins in a predictable way. A protein is a chain of amino acids, and there are 20 different amino acids. The genetic code dictates the sequence of amino acids, and therefore this information is easy to obtain. The sequence of amino acids determines how the protein will fold into its functional form, but it remains very difficult to predict how a given sequence of amino acids will fold.
The Urbach group seeks to develop an understanding of how to recognize a protein using only the information available in its amino acid sequence. We use “synthetic receptors”, which are relatively small molecules that have their own internal cavities in which other molecules can fit. Synthetic receptors work like antibodies but are less expensive, more stable, and easier to study. Few synthetic receptors, however, can bind with the strength and selectivity of antibodies, but we have discovered that the cucurbit[n]urils can do this. Cucurbit[n]urils are donut-shaped molecules that have a hydrophobic inner cavity with polar entrances on either side. Cucurbit[n]urils bind many organic cations by including the nonpolar portion of the molecule within the hydrophobic cavity, while the cationic groups interact with the polar entrances. Cucurbit[n]urils have gained a lot of attention in recent years due to their ability to function in water, their low toxicity and high stability, and their ability to bind to wide range of interesting molecules.
We discovered that cucurbit[n]urils can bind to the aromatic amino acids—tryptophan, phenylalanine, and tyrosine—when they are located at the first position in the protein chain. The nonpolar aromatic group binds inside the cucurbit[n]uril cavity, and the positive charge at the tail end of the protein (the nitrogen-terminus) binds to the polar entrance. These structural features allow for cucurbit[n]urils to bind predictably to proteins based on the identity of the first amino acid in the chain. Our work continues to expand on this discovery by pushing the boundaries of affinity and selectivity in the sequence-based molecular recognition of proteins and developing tools for biochemistry and biotechnology.