Summary of Seventh Maria Goeppert Mayer Symposium Held at UCSD
(from the SDSC archives: http://www.npaci.edu/online/v6.8/mgm.html)

The Seventh Annual Maria Goeppert Mayer Interdisciplinary Symposium (MGM) was held at UCSD on March 2, 2002. The invited speakers -- chemists, chemical engineers, biochemists, and crystallographers -- continued the tradition of the Symposium with a group of talks on disparate topics that met, across disciplines in the common search for patterns of expression and interaction on a variety of temporal and spatial scales.

The Symposium has become an annual tradition at UCSD since it was first organized in 1996 by SDSC chemist Kim Baldridge (who is also an adjunct professor of chemistry at UCSD). Named in honor of 1963 Nobel prize winner Maria Goeppert Mayer, who taught at UCSD at the end of her career, the Symposium also seeks to recognize the interdisciplinarity that was the hallmark of her work. Each year, the one-day Symposium features a group of invited speakers followed by an afternoon poster session displaying recent research by undergraduates, graduate students, and postdoctoral researchers in the labs of the speakers and at other campus labs across the country.

This year's speakers included biochemists, chemists, chemical engineers, and materials scientists, with topics ranging from design of anti-HIV drugs through island formation by atoms deposited on surfaces to mixed quantum/classical models of enzyme activity. Baldridge welcomed the audience of about 250. The speakers and their topics were:

Jacquelyn Gervay-Hague (Professor of Chemistry, University of California, Davis)
Development of alternative therapies to prevent HIV infections
Jacquelyn Gervay-Hague obtained her doctoral degree from UCLA, was an NIH postdoctoral fellow at Yale, then taught at the University of Arizona until joining the UC Davis faculty as professor of chemistry. "I am interested in chemical solutions to biological problems," said Gervay-Hague, whose work has focused on the complex biochemistry of carbohydrates (and who serves on the editorial boards of two journals devoted to the topic). She discussed one application of carbohydrate chemistry that is under development in her lab: a possible alternative therapy to prevent the HIV infection that leads to AIDS.

One receptor on cells that enables HIV to enter them is called CD4 -- and there is a lot of CD4 on T lymphocytes. One of the morbid signs of AIDS is a plunge in T cell counts. The CD4 enables HIV to enter the cell by binding to the HIV viral envelope glycoprotein known as gp120. At the same time as it attacks T-cells, HIV can also attack other cells that do not have CD-4. In this case, the cells interact with gp120 also, via a lipid called galactosyl ceramide (GalCer). The strategy of Gervay-Hague's group is to create analogues to GalCer that can interfere with the initial recognition events between gp120 and host cells, specifically by competing for gp120's dubious favors.

Using both the standard ELISA assay and a technique known as total internal reflectance fluorimetry, the group has measured the binding strength of gp 120 with GalCer and analogues GluCer and LacCer, both found in human cells, and two other analogues not found in human cells but able to bind to gp120. They found some of these compounds will bind sufficiently strongly with gp120, and they are now looking for the best method of delivering such compounds to appropriate sites in the body where they can compete for HIV's attention and prevent HIV from binding and then entering the body's own cells. They are collaborating with other groups at UC Davis and at the University of Arizona, and the work has been funded by NIH, Eli Lilly, the Sloan Foundation, and the American Foundation for AIDS Research (AmFAR).

Gervay-Hague was named an Eli Lilly Grantee in 1997 and was appointed an Alfred P. Sloan Fellow in 1998. In 1999, she was awarded the Horace S. Isbell Prize of the Carbohydrate Division of the American Chemical Society. She was introduced and the session was chaired by Dr. Sangeeta N. Bhatia, M.D., an assistant professor in the UCSD bioengineering department.

Rowena G. Matthews (Distinguished University Professor of Biological Chemistry, University of Michigan)
Methylenetetrahydrofolate reductase: the biochemical phenotype of a common polymorphism
Rowena Matthews has been for many years the G. Robert Greenberg Distinguished University Professor of Biological Chemistry and senior research scientist in biophysics at the University of Michigan, where she obtained her doctorate after graduating from Radcliffe College. Matthews is a Fellow of the American Association for the Advancement of Science. She discussed recent research, published in the Proceedings of the National Academy of Sciences and widely noticed in scientific and popular journals, that has called attention to the role of folic acid in the diet. Folic acid aids in preventing elevated concentrations of homocysteine in the blood, a condition that leads to increased risk of heart disease, stroke, and birth defects in humans.

Matthews and her group identified the mechanism that leads to a single nucleotide mutation (from cytosine to thymine) in the catalytic subunit of an enzyme with the breathtaking name of methylenetetrahydrofolate reductase -- MTHFR, for short. Individuals having this mutation (about 15 percent of the population of the United States) are particularly susceptible to deficiency in the vitamins folic acid and riboflavin -- and to the complications of elevated homocysteine.

The group purified MTHFR from pig liver, a complex process that took a week to reduce 4 kg of liver to 1 mg of MTHFR. They then used electron microscopy facilities at Brookhaven National Laboratory to obtain a picture of the gross structure of MTHFR. It turned out to be a dimer, Matthews said, with a regulatory region and a catalytic region. With collaborator Rima Rozen at McGill University, the Matthews group then cloned human MTHFR and compared the sequence with MTHFR from two prokaryotes and several other eukaryotes. Only the eukaryotes (pig, yeast, roundworm, and human) have the regulatory region in their MTHFR, and the group was able to find the locus of the mutation from C to T, at position 677 in the catalytic region. The C677T polymorphism leads to weakened binding of the essential flavin cofactor on MTHFR and thus leads to elevation of levels of homocysteine.

To the riddle of why the mutation persists if it is so deleterious, Rozen's group found that it may also confer protection against some forms of cancer, provided there is an adequate dietary intake of folic acid. Matthews and her group are now awaiting the results of studies of whether increasing intake of riboflavin and folic acid via diet and supplementation can prevent the adverse consequences of the mutation in people who have it.

Matthews received the William A. Rose Award from the American Society of Biochemistry and Molecular Biology in 1999 and the Repligen Award for the Chemistry of Life Processes from the Biological Chemistry Division of the American Chemical Society. She was introduced and the session was chaired by Joanne Stewart, a visiting assistant professor from Hope College in Pennsylvania who is spending a sabbatical year working with UCSD chemist Clifford Kubiak.

Kristen Fichthorn (Professor of Chemical Engineering, Pennsylvania State University
Island nucleation in thin-film growth: Exploring and exploiting the substrate-mediated interaction
Kristen Fichthorn graduated from the University of Pennsylvania, then attended the University of Michigan, from which she received her doctorate in 1989. She became an assistant professor of chemical engineering at the University of California, Santa Barbara, before joining the chemical engineering faculty at Penn State, where she has won awards for outstanding research and curricular innovation. In 1998, she was named an Alexander von Humboldt Research Fellow. She uses a panoply of computational methods to study the phenomena of materials on surfaces and interfaces. In particular, she and her colleagues are seeking an understanding of the ways in which layers of atoms are added to surfaces in the process called thin-film epitaxy, which is used to create materials having various useful properties (optical, catalytic, and magnetic, for example).

When atoms are deposited on a surface of the same or other atoms, they arrange themselves on the surface in a wide variety of patterns. The first patterns to appear are islands of the adatoms (deposited atoms). Fichthorn is seeking a quantitative understanding of the variety of island morphologies (sizes, shapes, spatial distributions), "each the signature of an intricate kinetic balance," she said. Working with colleagues Michael Merrick of Penn State and Matthias Scheffler of the Fritz Haber Institute in Berlin, under funding from the National Science Foundation and the von Humboldt Foundation, Fichthorn has been able to show what physical processes govern varieties of island nucleation under various conditions far from equilibrium.

Her group uses both first-principles density functional theory (DFT) and kinetic Monte Carlo calculations to model the deposition of adatoms like silver on platinum, silver on a mixture of silver and platinum, and silver on silver. Standard island nucleation theory, based on nearest-neighbor interactions, fails to explain all the phenomena seen in these cases, Fichthorn said. She believes that both long-distance interactions and elastic interactions are mediated by the specific deposition surface, leading to departures from the basic theoretical predictions. She modeled pair, trio, and higher order interactions using DFT, then turned to kinetic Monte Carlo simulations to approximate the multitude of diffusion processes involved in forming adatom patterns. "Edge diffusion, aggregation, nucleation, terrace diffusion -- these are all distinct processes occurring at different rates," she noted.

One conclusion from the modeling is that it may well be possible to tune in on the size of the first islands formed and then to control their growth and form by various means; in particular, the modeling showed that nucleation was extremely sensitive to variations in the temperature of the overall process. "The ability to control and manipulate the island nucleation process may be key in the future to obtaining new materials with highly specific properties," Fichthorn said. She was particularly excited by the variety of applications that may be developed to control the formation of materials used in fiberoptics and optoelectronics.
Fichthorn was introduced and the session was chaired by Wibke Sudholt, a postdoctoral researcher working with Baldridge and the group of Andrew McCammon at UCSD.

Sharon Hammes-Schiffer (Schaffer Associate Professor of Chemistry, Pennsylvania State University)
Molecular dynamics studies of the relation between enzyme motion and activity
Sharon Hammes-Schiffer graduated from Princeton and received her doctorate in chemistry from Stanford University in 1993. After two years of postdoctoral research at AT&T Bell Laboratories, she became Clare Booth Luce Assistant Professor of Chemistry and Biochemistry at the University of Notre Dame. While there, she was the recipient of an NSF Career Award (1996), a Faculty Enhancement Award from Oak Ridge Associated Universities (1998), an Alfred P. Sloan Fellowship (1998), and a Camille Dreyfus Teacher-Scholar Award (1999). She joined the faculty at Penn State in 2000 and has since been appointed a senior editor of the Journal of Physical Chemistry, among other honors.

Hammes-Schiffer and her group study charge transfer reactions, which play a vital role in a wide range of chemical and biological processes. Her research applies newly developed theoretical and computational methods to the study of chemically and biologically important reactions. The aim is to elucidate charge transfer mechanisms and predict rates and kinetic isotope effects for comparison with experiments. They have recently elaborated a multistate continuum theory in which solutes are described by a multistate valence-bond model, solvent is represented as a dielectric continuum, and the active electrons and transferring protons are all treated quantum mechanically.

Ideal chemical processes are often represented as smoothly crossing an energy barrier from reactants to products, but important reactions may actually cross and recross the barrier several times. This appears to be the case for liver alcohol dehydrogenase (LADH). This enzyme catalyzes the reversible oxidation of alcohols to their corresponding aldehydes or ketones in the presence of a cofactor called nicotinamide adenine dinucleotide (NSD+). In the body, reactions involving LADH may play a role in bringing about the conditions associated with alcoholism (e.g., ketoacidosis and hypoglycemia). Hammes-Schiffer and her group focused on the LADH-catalyzed oxidation of benzyl alcohol.

LADH is a 75,000-atom dimeric system. Hammes-Schiffer modeled the motion of the enzyme at the 148-atom active site and in the entire solvated molecule. The calculations made by the group support the idea that alcohol deprotonation occurs before hydride transfer, and that this facilitates the hydride transfer by lowering the energy barrier to hydride transfer. Specifically, she found hydrogen tunneling through the energy barrier about half the time, while isotopes (deuterium and tritium) behaved more classically. This insight may be of particular use in designing means to slow down or inhibit the reaction entirely. The audience viewed movies of the dynamical trajectories of the reactions of LADH and another enzyme, DHFR, in which barrier recrossing proved to be even more important. The calculations show the close connection between motions of an entire enzyme and specific charge transfer reactions occurring at an active site, and the group is now developing new methodologies to deepen the quantum treatment of specific hydrogen atoms and permit closer comparison with experimental data. "We also hope to apply our methods to glucose oxidase, which catalyzes reactions as a biosensor in diagnostic kits for monitoring blood glucose in diabetics," Hammes-Schiffer said.

Hammes-Schiffer was introduced and the session was chaired by Vanda Glezakou, a postdoctoral researcher in the group of Peter Taylor at SDSC.

Ada E. Yonath (Professor of Structural Biology, The Weizmann Institute, Israel)
Antibiotics targeting ribosomes
Ada E. Yonath is the Martin S. Kimmel professor of structural biology and director of the Helen and Milton A. Kimmelman Center for Biomolecular Structure and Assembly and the Joseph and Ceil Mazer Center for Structure Biology, all at The Weizmann Institute in Rehovot, Israel. She is also the leader of a group at the Max-Planck Research Unit for Ribosomal Structure in Hamburg, Germany.
As one of the world's premier crystallographic investigators of the three-dimensional structures of complex proteins, Yonath and her group are now addressing a major problem in modern therapeutics: resistance to antibiotics.

Most antibiotics acton the cellular organelle called the ribosome. Ribosomes catalyze the translation of genetic code into proteins. They are made up of assemblies of RNA and proteins, usually arranged in two subunits that associate to perform protein biosynthesis. A large subunit creates peptide bonds and provides the path for emerging, nascent proteins. The smaller subunit controls the fidelity of base-pairing and initiates the biosynthetic process.

Yonath's group used synchrotron facilities at EMBL and DESY in Germany to obtain high-resolution structures of ribosomal subunits from pathogenic bacteria -- major targets for antibiotics. Then, using molecular dynamics methods, the group found the binding sites on the subunits for a range of antibiotics. The ability to localize the precise binding sites of various antibiotics enables the group to study not only the mechanisms by which antibiotics interfere with bacterial activity but also how the ribosomal subunits order and control their operations during biosynthesis.

Yonath was introduced and the session was chaired by Julie Mitchell of SDSC, an independent staff scientist.
In the afternoon session, 32 posters were presented detailing work cutting across the boundaries of chemistry, chemical engineering, physics, biophysics, and biochemistry, addressing many problems posed in what is becoming a typically interdisciplinary fashion in a growing number of laboratories. The award for best poster went to Sherri Lillard of UC Riverside. Second place was shared by Wibke Sudholt and Nathan Ludki, both of UCSD, and third place went to Jon Loren of UCSD.

"We are looking forward to extending the annual MGM Symposium across political boundaries as well," Baldridge said. She and an organizing committee are hoping to engage international audiences via satellite symposia based at foreign universities, culminating in events linked to the 100th anniversary of Maria Goeppert-Mayer's birth in 2006. "We are seeking to engage a spectrum of new committee members and corporate sponsors in these efforts," she added. Interested readers should contact Baldridge at kimb@sdsc.edu.