This page is designed for undergraduate students interested in research at Trinity University. Please contact Dr. Urbach for further details or to discuss research opportunities.

Bioorganic chemistry uses techniques in organic chemistry, such as synthesis and NMR spectroscopy, to study proteins, nucleic acids, and other biological molecules. The overarching goal is to understand the structure and reactivity of biomolecules. A major thrust of this field is to design new compounds that can selectively bind to (or “recognize”) biomolecules, thus giving us a way to change their reactivity. Drugs do this—they recognize their specific target proteins, bind tightly to them, and inhibit their activity. One of the ultimate challenges of bioorganic chemistry is to understand enough about intermolecular interactions that we can design a molecule to bind to any protein we want. Another important goal is to make compounds that act as “sensors” by binding to and revealing the presence and quantity of a specific biomolecule, either by changing color or by producing light or electricity. Sensors are key components of medical diagnostics, such as a device that can measure the amount of a hormone in a patient’s blood.

A view of the inside of the binding pocket of the enzyme Human Carbonic Anhydrase II, with a small drug molecule (an arylsulfonamide) tightly bound. The surface of the protein cavity is labeled with the amino acid residues and zinc ion that we believe are important for molecular recognition. This is the most highly studied enzyme-drug system, and we still don't completely understand it. The structural coordinates were taken from Grzybowski et al. (2002) Proc. Natl. Acad. Sci. USA 99, pp. 1270-1273 and rendered by George Kaufman (Harvard University) using Pov Ray.

Students in the Urbach laboratory design, synthesize, and study compounds that can recognize and bind tightly to specific peptides in aqueous solution. Peptides (small proteins) are short, linear chains of amino acids, and since there are 20 common amino acids, even small peptides can have a wide variety of structures and properties. Trinity students Meghan Bush (class of 2005) and Nicole Bouley ('07) discovered that the donut-shaped molecule we call Q8 (see figure below) can bind tightly and specifically to certain peptides (X in the figure), and what’s exceptionally cool is that this happens in water! This might seem like a given since all biological chemistry happens in water, but the fact is that the vast majority of synthetic compounds don’t even dissolve in water, and it is particularly rare to find one that can dissolve in water and bind tightly to specific peptides. What’s more, when certain peptides bind to Q8, the sample turns orange, and so we can use this system to sense the presence of a peptide and to tell us (by the intensity of color) how much peptide is present.

Summary of the results in Bush, Bouley, and Urbach, Journal of the American Chemical Society, vol. 127, pp. 14511-14517. The large cyclic molecule (Q8) can specifically encapsulate the amino acid tryptophan (X), and it binds most tightly to tryptophan located at the N-terminus of a peptide chain, thus demonstrating sequence-selective recognition.

 

Lisa Ryno (formerly Heitmann) was able to grow crystals of the Q8•Peptide complexes, so in collaboration with Dr. Alex Taylor and Prof. John Hart at UT Health Science Center in San Antonio, we determined the high-resolution structures of these complexes by X-ray crystallography. The structures (show below) reveal that Q8 binds selectively to tryptophan and phenylalanine when they are located at one end (the N-terminus) of a protein because the positive charge located at the N-terminus interacts with the negatively charged groups on Q8.

 

Q8 is unusual in that it binds two different guests at the same time. We made use of this property to create molecules with two copies of Q8 so that we could bind to peptides containing two tryptophan residues. In the scheme shown below, a scaffold containing two copies of an anchor molecule (red) was used to bring two copies of Q8 together. The resulting self-assembled receptor then binds peptides containing two tryptophans with higher affinity than single-site receptors. This approach is very similar to that found in Nature, where proteins embedded in the cell membrane are held together noncovalently and will work together to bind to other cells using multiple points of contact. This system makes possible many interesting projects, which are currenlty being pursued by students in the group.

Students in the group learn a variety of techniques, even in their first year of college. These include: 1) organic and solid-phase synthesis to make peptides and other small molecules; 2) NMR and circular dichroism spectroscopy, mass spectrometry, and X-ray crystallography to characterize molecular structure; 3) microcalorimetry, stopped-flow spectroscopy, and capillary electrophoresis to measure the thermodynamics and kinetics of binding; and 4) UV-visible and fluorescence spectroscopy to study electronic properties. This combination of methods and approaches offers students a breadth of technique and depth of study that is excellent training for future work in a wide range of areas.

For further information and to discuss research opportunities in the group, please contact Dr. Urbach.