MANUFACTURING

By Katherine Caponi -- NCSA is arming a team of young scientists with the supercomputing resources necessary to engage in the battle against cancer. This team of undergraduate physical, biological, and computational chemists at New York's Hamilton College joins the front line in computational research on enediynes, naturally occurring molecules commonly called biological warheads for their ability to bind to and split tumors' DNA backbones. Using NCSA's SGI Origin2000 supercomputer, the students are contributing knowledge of new cancer treatments and using computational chemistry in an authentic team research setting. Scientists became interested in the antitumor activity of enediyne antibiotics such as dynemicin, calicheamicin, and esperamicin because of the molecules' low thermal barriers to Bergman cyclization. Bergman cyclization is a reaction in which the enediyne converts to an intermediary benzene diradical, an aromatic ring missing two carbon-hydrogen bonds. When the molecule is in the intermediary diradical state, it can forcibly extract hydrogen from deoxyribose carbons to split DNA, resulting in the death of the cancerous cell. The temperature barrier is the amount of energy that must be applied to the molecule to cause a reaction. This level is particularly important to drugs' effectiveness because it determines whether Bergman cyclization will occur at human body temperature. Many scientists are trying to synthesize or computationally design molecules that only cyclize when they've taken on an additional hydrogen ion, a process that occurs readily in acidic solutions. The challenge is to find or create an enediyne-containing molecule that is completely unreactive under the normal pH of a healthy cell, yet takes on an additional hydrogen ion in acidic cancerous cells and becomes reactive. C. David Sherrill of the Georgia Institute of Technology, an expert in the field of enediyne chemistry, reacted to the impact of the Hamilton team's work, "[Their research] tells us something about exactly how these drugs react, and this information may be useful in designing new anticancer drugs that are more effective. It is very exciting that computational simulations are starting to give us insight into these difficult-to-study molecules." The team at Hamilton is learning to manipulate cyclization temperatures, increasing the chances that a more effectively targeted class of antibiotics with low toxicity to healthy cells will be developed. The ultimate goals of the undergrads are to observe the drug-induced extraction of hydrogen molecules, which splits the DNA; to find and manipulate the thermal barrier for cyclization; and to view the natural processes that occur in conjunction with the reaction. To accomplish their goals, the team is using complex calculations with pinpoint accuracy on the warhead, or the six-carbon enediyne portion, of the molecule. They perform slightly less complicated calculations on the next crucial layer, the body of the molecule, which is the portion tied up in rings right around the enediyne. The body is critical in lowering the barriers for cyclization. The molecule's body also contains the triggering mechanism that prevents cyclization before the drug is located in DNA. The arms of the molecule, which require the lowest level of calculation, are side chains that jut off the body and help a drug bind to DNA. Applying varying levels of theory to different parts of the molecule is called the ONIOM method. ONIOM method is a computational method developed by Keiji Morokuma, a computational chemistry pioneer at Emory University. ONIOM, created in part using Alliance supercomputing resources, lowers costs of research by applying supercomputing allocations with varying levels of precision to different layers of the molecule studied. This strategy allows the Hamilton team to focus their efforts and resources on the warhead parts of the molecule that are most important to understanding the diradical formation. Hamilton's Dreyfus Postdoctoral Teaching Fellow and the project's principal investigator, Steven Feldgus, requested a 40,000-hour allocation of supercomputing time for the research. He has worked extensively with NCSA resources in the past, beginning with projects in graduate school, and has applied for and used over 100,000 supercomputing hours for multiple projects in the last three years. Feldgus began work on the enediyne project during the spring of 2001. He performed all beginning calculations between January and mid-May and then stepped into an almost purely advisory role, training the undergraduates and supervising their computations. He said of the project, "Even though some of our students are freshmen and sophomores, we've got them working on a real chemical problem using world-class computers, and we've got them hooked. When it comes to getting students to learn and get excited about research, we're doing as well as anyone. And that's the most satisfying part of this work for me. And who knows? Perhaps one of these students will go on and someday make a major breakthrough in the field. That would just be gravy." Chantelle Rein, David Kelland, and Beth Hayes joined the project as the undergraduate team in summer 2001. Rein began studying the effects of substituting different parts to esperamicin molecules, one class of enediyne antibiotics, to raise and lower the barriers to Bergman Cyclization. Rein will be presenting the results of her work at the Sanibel Symposium, a quantum chemistry conference in St. Augustine, FL, this February. As the lone freshman on the team, Kelland's objective is to test the accuracy of the ONIOM method applied to Bergman Cyclization by comparing ONIOM results to enediynes where the thermal barriers to cyclization are already known experimentally. Hayes is looking at possible reaction pathways between oxygen and a small diradical molecule. George Shields, a co-principal investigator for the project, says that this hands-on approach to education is an essential element in turning students into scientists, "We feel that the best kind of teaching stems from the mentoring and one-on-one interactions between faculty and students in a small research group. Science has always worked best with the apprenticeship model, and we give undergraduates a chance to find out if they want to become research scientists before they have to make a decision on whether to attend graduate school." ----- Steven Feldgus' homepage: http://www.chem.hamilton.edu/faculty/feldgus.html Story used courtesy of NCSA's Access