David E. Draper
Johns Hopkins University
3400 North Charles St.
Baltimore, MD 21218
Ph.D. - University of Oregon
"RNA folding” has become a vigorous area of research as many unexpected and important functional roles have been discovered for RNA molecules. My lab is using a variety of physical techniques to ask questions about fundamental principles of RNA folding energetics.
Much of our work in recent years has been concerned with electrostatic aspects of RNA. Folding of an RNA tertiary structure is opposed by the unfavorable free energy needed to bring negatively charged phosphates into proximity, and it has long been known that Mg(2+) is much more effective than monovalent ions at reducing the electrostatic free energy of RNA tertiary folds. We have developed a theoretical framework which successfully accounts for the special properties of Mg(2+), and have also developed the thermodynamic background and experimental methods for measuring the overall free energy of Mg(2+) - RNA interactions. The agreement between theory and experiment so far is gratifying, though we continue to explore RNA systems that might require more sophisticated theoretical developments. In particular, the energetics of Mg(2+) ions that are buried within the RNA is challenging to characterize. We are also working with a computational group to characterize the behavior of monovalent ions around unusual RNA structures
Several aspects of RNA folding occupy the lab at present. One problem which has emerged from the Mg(2+) - RNA studies is the nature of the ensemble of RNA structures (containing both helical and single stranded segments) from which tertiary folding takes place. We are using a combination of molecular modeling, computation, and experiment to approach this problem. We are also asking how changes in hydration- of both ions and the RNA surface- might influence RNA stability, using calorimetry and other methods. Another areas of interest is the dependence of RNA stability on osmolytes, small organic molecules that cells use (along with ions) to regulate their water content in response to changes in the composition of the external medium. Virtually all osmolytes destabilize RNA secondary structure but many stabilize RNA tertiary structure. Part of the motivation for these studies is our interest in the in vivo stabilities of functional RNAs, but we also find that osmolytes can be useful tools for probing the interactions of RNAs with water and ions.