With support from the Chemical Measurement and Imaging program, Prof. David Dearden and his group at Brigham Young University are devising new approaches to the detection and characterization of prototypical molecular devices based on pumpkin-shaped molecules (named cucurbiturils, after the Latin name for "pumpkin") that constitute some of the smallest possible containers. The methods being developed complement existing techniques by providing better sensitivity. They include the first infrared multiphoton dissociation studies of these materials, essentially using infrared laser light to take "snapshots" that reveal the way the devices fit together. Cucurbiturils and related "containers" are being investigated in other laboratories for potential applications in such diverse areas as components of molecular machines; in drug encapsulation, protection, and delivery; and in sensitive new analytical assays such as the direct detection of insulin levels in the blood (relevant to the detection and treatment of diabetes). It is widely recognized that the binding properties of cucurbiturils are sensitively dependent on solvents and counterions, yet the reasons for this dependence are not clearly understood. Hence, these fundamental gas-phase studies of structures in the absence of solvent and counterions are vital to gain understanding needed to facilitate future applications, addressing questions such as how trapping molecules inside the cavity affects the binding of cations on the rims, the mechanism of exchange of bound/trapped species, and the origin of the large shifts in acidity that occur for trapped guests.
The characterization methods being developed will enable applications of this "supramolecular" chemistry that may ultimately impact manufacturing, computing, and medicine. The techniques will also be immediately useful to biomolecular studies involving nature's "molecular machines," proteins. The work will also have important educational benefits. Graduate students will be trained in advanced techniques for high performance mass spectrometry that are vital for the biotechnology industry and the emerging field of proteomics. A parallel aim is to attract talented undergraduate students to chemical research. Toward this aim, the instrumentation supported is also used in undergraduate courses in analytical and physical chemistry, providing direct experience with advanced techniques most students would not otherwise see outside of graduate school.
Measuring Molecular Shapes By Monitoring Molecular Collisions The main goals of this project deal with creating new ways to measure the shapes of molecules. Molecular shape is crucially important to determining whether and how molecules react with each other. This might seem like a mysterious detail until you realize that all the material things around us, including all living things, are made of molecules and the fitting together of these molecular building blocks depends crucially on their shapes: just as with toys, square molecular "pegs" do not fit well into round molecular "holes." Even though they contain the right atoms attached to each other in the correct order, molecules such as proteins folded into the wrong shapes can even cause disease (although it is not fully understood, Alzheimer's disease is one that likely involves protein misfolding). So being able to determine molecular shapes and understanding what controls shapes is an important problem. Our work involves basic scientific efforts to build tools to do this. Molecules are too small to see or touch, so how can shapes be measured? The methods we have developed do it by allowing the molecules to collide with well-understood gas molecules inside an instrument called a Fourier transform ion cyclotron resonance mass spectrometer. This instrument is capable of detecting groups of charged molecules moving together. When collisions occur, the colliding molecule is removed from the group and the resulting signal strength decreases. We analyze this loss of signal and use it to determine the size of the colliding molecule: large molecules collide frequently and are quickly lost from the group, whereas smaller molecules are hit less frequently and remain in the group for longer times. While this is only a crude measure of shape, it is often enough to distinguish between just a few shapes that are chemically possible. So far, for example, we have looked at molecules called cucurbiturils (named after the Latin word for "pumpkin"-see the picture) that have shapes like pumpkins with their tops and bottoms cut off and all but the outer shell removed. Other molecules can bind with the cucurbiturils to form a two-molecule "complex," and may either be stuck to the exterior of the "pumpkin" or be bound inside the hollow interior. Our new techniques measure larger sizes for the exterior complexes than for those with the second molecule bound on the inside of the cucurbituril "pumpkin" (and we now know that nature generally favors the "interior" complexes when the sizes are right). Someday, molecules like these may become parts of machines built from molecule-sized parts to do high-performance computing or to diagnose and treat disease. As a bonus, we can already make these measurements with microscopic amounts of sample using instruments that need only inexpensive modifications from those that are already on the market. We have made our work available to the public so far in 7 scientific journal articles, 2 scholarly dissertations, and 11 presentations at scientific meetings. While the work itself is important, it is equally important to train the next generation of scientists so that problems like the ones we are now working on, as well as future problems not yet imagined, can be solved. All of the work in this project was carried out in a university setting with scientific training as a primary goal. Six graduate students and seven undergraduate students (who will themselves go on to become scientists, doctors, dentists, and other professionals) were directly trained in this project; all of them have helped achieve the results we report. In addition, stories from this research are regularly used to illustrate scientific ideas and to generate interest in science in general and chemistry in particular with large numbers of undergraduate students and members of the general public (more than 1500 during this project). Even though synthetic molecular machines are hypothetical, the practical training benefits are happening right now.
