Christine Dunham Receives ASBMB Young Investigator Award

Dr. Christine Dunham, associate professor of Biochemistry at the Emory University School of Medicine and Associated Faculty in Chemistry, has been awarded the American Society for Biochemistry and Molecular Biology Young Investigator Award. The award includes a $5,000 cash prize and recognizes outstanding research contributions to biochemistry and molecular biology by a scientist who has no more than 15 years postdoctoral experience. In addition to her research and teaching, Christine is an editorial board member of the Journal of Biological Chemistry, which the ASBMB publishes and has served on the ASBMB’s meeting program planning committee

Congratulations, Christine!

Ian Pavelich Awarded ARCS Fellowship

Ian Pavelich
Ian Pavelich

Ian Pavelich (Dunham Group) has been awarded an Advancing Science in America or ARCS Fellowship. The ARCS Foundation advances science and technology in the United States by providing financial awards to academically outstanding U.S. citizens studying to complete degrees in science, engineering and medical research. The awards are focused on helping researchers at the startup or “seed stage” of their work and discovery.

Ian’s project is titled “Molecular mechanisms of antibiotic tolerance.” “The project focuses on identifying the molecular mechanism for how pathogenic bacteria confer an antibiotic tolerance phenotype or behavior without the requirement for genetic mutations,” says Ian. “Currently, we’re attempting to identify how different stresses, like classes of antibiotics, activate different enzymes that trigger antibiotic tolerance.” The research has potential implications for the future of public health: “As modern medicine would be impossible without the use of antibiotics, further investigating these novel systems as potential new antimicrobial strategies is incredibly important.”

The ARCS Award is an unrestricted $7,500 award given directly to the scientist and may be renewed for up to three years. When asked how the ARCS Award will affect his work, Ian says: “I think that ARCS will provide a layer of flexibility in how we choose to answer the questions targeted by my research. I am extremely grateful that the ARCS committee granted me these funds, and with them I aim to expand the scope of my studies using more interdisciplinary approaches. I also plan to use funds to attend a range of diverse conferences.”

Outside the lab, Ian has been involved in outreach at Emory, working on a chemistry event during the annual Science Olympiad for area high school students that focused on fundamental gas laws and their quantitative uses. Ian’s ties to Emory go beyond chemistry, too. This month, his partner will be joining the Political Science Department graduate program at Emory: “we’ll be doing our PhDs side by side!”

Congratulations, Ian!

Research Spotlight: A Unique Method for Studying Enzymes

Morgan in the lab. Photo provided by Morgan Bair Vaughn.
Morgan in the lab. Photo provided by Morgan Bair Vaughn.

By: Morgan Bair Vaughn (Dyer Group)

Enzymes are responsible for catalyzing a myriad of reactions necessary for life. Because enzymes play such an important role in human physiology, they are often targets for drugs and disease treatments. Naturally occurring enzymes are capable of catalyzing a wide variety of reactions, but imagine if we could design an enzyme to catalyze any reaction we wanted. We would be able to create new antibiotics easily to combat antibiotic resistance or to quickly synthesize chemicals for industrial applications. Scientists have made a lot of progress towards creating new enzymes, yet there are still roadblocks. Modifying existing enzymes through directed evolution is inefficient and limited by the need for high throughput screening methods. Conversely, in the case of rational design, we are missing key information for the technique to work at its full potential.

My research works to fill in the gaps in our knowledge to allow for the efficient development of new enzymes. A large portion of the scientific community focuses on determining the structure of enzymes and how the structure impacts function. While this work is enormously important, it doesn’t tell the full story. One major aspect that is often overlooked when examining structure-function relationships is that enzymes are dynamic molecules. This means that they physically move, bend, wiggle, and change shape during catalysis.

To study enzyme dynamics, I use temperature jump spectroscopy. There are only a few labs around the world that use this technique, and even fewer that use it to study enzymes. Temperature jump spectroscopy relies on rapidly initiating a change in equilibrium. For example, my samples contain enzymes and ligands. As determined by the equilibrium constant, some of the ligand is bound and some ligand is free in solution. The sample starts at equilibrium at a specified temperature. Then, a laser pulse is used to rapidly heat a small portion of the sample. The system must relax to a new equilibrium at the higher temperature. Since ligand binding is an exothermic reaction, there will be a net flux of ligands dissociating from the enzyme. However, as a system relaxes to a new equilibrium it will shift in the forward and reverse directions providing information about both processes. From this data I can determine the rate at which ligands are binding and unbinding, accompanying enzyme motions, and even conformational changes unrelated to ligand association. These changes occur on the microsecond timescale.

Although temperature jump spectroscopy could be applied to any number of enzymes, so far I’ve studied one enzyme in particular, dihydrofolate reductase (DHFR). It is a small ubiquitous enzyme that is well known for changing conformations during its catalytic cycle. Thus, it is a good starting place for understanding enzyme dynamics. Furthermore, DHFR is an important enzyme for nucleic acid synthesis. Since nucleic acid synthesis is necessary for cellular replication, DHFR inhibition is a strategy for anticancer and antibacterial agents.

Understanding the motions of DHFR could lead to the development of new inhibitors to combat resistance developed in certain cancers. The technique I use can be applied to other enzyme systems as well. By studying multiple enzymes we can build an understanding of enzyme motions in general, which can then be used to inform computational simulations for rational enzyme design. This would ultimately allow us to efficiently design new enzymes as well as new drugs.

Further Reading

Reddish, M. J.; Vaughn, M. B.; Fu, R.; Dyer, R. B. Ligand-Dependent Conformational Dynamics of Dihydrofolate Reductase. Biochemistry 2016, 55 (10), 1485-1493.