Joel R. Tolman

Associate Professor

Remsen 239
410-516-8022
jtolman@jhu.edu

Biography

Within the past two decades, Nuclear Magnetic Resonance spectroscopy (NMR) has become a powerful technique for the study of macromolecular structure and dynamics in the solution state. Research in my lab will be concerned with both the development and application of novel NMR techniques for studying the complex interactions that underlie biological function. Of particular interest are studies of molecular dynamics, the nature of intermolecular recognition and the quaternary organization of multi-domain protein systems.

The full repertoire of multidimensional NMR methodology will be employed to study these problems, including spin relaxation, scalar coupling, NOE, and hydrogen exchange experiments. However, the primary approach will be centered around recently developed techniques for the measurement of Residual Dipolar Couplings (RDCs) in macromolecules. These RDCs, which are normally averaged to zero in solution, are made observable by introducing a very weak degree of alignment of the biomolecule relative to the magnetic field. This alignment is typically achieved by dissolving the protein or nucleic acid along with a suitable co-solute, such as bacteriophage particles. The resulting RDCs are relatively easily measured and represent an abundant source of highly precise information on the relative orientations of different internuclear 'bonds' within the molecule. Intriguingly, RDCs also exhibit sensitivity to molecular motions on the nsec-sec timescales, during which many functionally important motions occur. These motional timescales have traditionally been very difficult to access experimentally, and thus a major objective will be to develop RDC-based techniques to enable the study of these motions.

One of the applications of these techniques will be to investigate the quaternary organization of tetrameric ubiquitin. Tetramers of the protein ubiquitin can assume a multi-faceted role in cellular signal-transduction mechanisms, which depends on how they are linked together. A major goal will be to gain insights into the nature of this important and versatile signal through studies of its solution state conformations. In addition, efforts are ongoing to develop methodology for the simultaneous determination of both the 3-dimensional structure and a detailed description of the dynamics of a protein. A closely related objective is to develop the capability of using NMR to rapidly determine the backbone fold of a protein to moderate resolution, which would represent an important contribution to current structural genomics initiatives.