Applying NMR to biological problems

Interview with Professor Arthur Palmer

Arthur Palmer, the Director of NMR Spectroscopy at the New York Structural Biology Center and Professor of Biochemistry and Molecular Biophysics at Columbia University, talks about his research into protein dynamics and how it applies to the biomedical field.

Please tell us a bit about your current areas of research.

My main research interest is in using NMR to study relaxation in proteins and other biological macromolecules. I developed this interest during my postdoc with Peter Wright at the Scripps Research Institute, and it has been the focus of the work in my lab for the entire 22 years I have been at Columbia. Our current focus is on areas in protein folding, molecular recognition by proteins and also enzyme catalysis. NMR spin relaxation is one of the very powerful techniques in NMR for studying conformational dynamics in proteins or chemical kinetic processes.

Can you share some recent results of your research?

I’ll tell you about two studies we’ve completed recently that illustrate how we apply NMR to biological problems. In the first study, Dr. Ying Li, a postdoc in the group, used NMR relaxation to study the mechanism of dimerization of E-cadherin, a protein that’s critical in forming adhesion between cells in multicellular organisms. Her work was able to demonstrate that a hypothesized X-dimer was an important intermediate in the dimerization process, and that this dimer was important in setting the appropriate time scale for the biological function of the molecule.

In a second project, Dr. Michelle Gill, another postdoc in the group, collaborated with John Hunt and his student, Burçe Ergel, to study the enzymatic mechanism of AlkB, again using NMR spectroscopy, primarily spin relaxation, in conjunction with fluorescence experiments that Dr. Hunt’s group performed. The combination showed that a set of conformational dynamic changes in the protein control the multistep pathway that the enzyme has to take in order to carry out its biological function. Both of these projects illustrate the power of NMR spectroscopy in probing dynamic properties and proteins which we believe underline most of their functions.

What impact could your work have on biomedical research?

Impact, of course, is hard to quantify. We all like to think that our work is more important than it probably is in the grand scheme of things! However, at a meeting like the ICMRBS, it’s gratifying to see how many other scientists are using some of the techniques developed in my laboratory in their own research. For applications of our own, I think the major contribution has been showing how quantitative measures of protein conformational disorder and dynamics lead to detailed mechanistic understandings of protein function, and therefore malfunction, in disease or other sorts of pathological states.

How does instrumentation impact your research?

Instrumentation is critical. One major part of my research is devoted to developing new methods in NMR spin relaxation. This work requires and is driven by access to the latest technology, the latest generation of consoles, probes, and magnets. At the same time, applications to biological systems benefit from multiple static magnetic fields and NMR spectrometers ranging from 500 megahertz to 1 gigahertz and beyond. So, we need access to state of the art electronics, state of the art probes and state of the art magnets for everything that we do.



What technological improvements would have the biggest impact on your work?

Throughout the history of NMR spectroscopy, each step to a higher and higher magnetic field has opened up new opportunities and I think this is going to continue past 1 gigahertz and beyond. I look forward to the development of those technologies. At the same time, sensitivity is critical for biological work. The most important biological systems invariably are the lowest solubility, and the least stable. The more rapidly one can acquire high quality data, the more likely it is one can probe these systems. So, continued developments in sensitivity of probes and receivers is really very, very important and always will be. I, myself, am very interested in recent developments in field cycling spin relaxation work and I think this is a technology that holds great promise going forward. Then, of course, at the New York Structural Biology Center, we’ve recently installed a 600 megahertz DNP system, and we think this will be really transformative for people using the Center for their studies.