Professor of Molecular Physiology & Biophysics
Professor of Physics & Chemistry
Vanderbilt University Medical Center

Dynamics represent the fourth dimension linking protein structures to mechanisms. Proteins have parts that gate, bend, twist or catalyze a given reaction. These dynamic transitions take place on time scales ranging from picosecond side chain rotameric equilibria to millisecond rearrangements in cooperative protein complexes. Despite spectacular recent progress, the study of dynamics of membrane proteins and macromolecular complexes remain an immature area of research.

The main experimental focus in my laboratory is to understand the dynamic dimension of protein structures. We have developed and applied spectroscopic approaches based on paramagnetic or fluorescent reporter groups to characterize the collective functional or regulatory motion of protein secondary structures and domains. Highlights of our work include describing protein motion that coupling ATP hydrolysis to substrate translocation by transporters, hinge motion in T4 Lysozme, and single molecule detection of domain movement.

We use spin labeling with EPR spectroscopy as our major experimental tool to describe protein dynamics in energy transduction systems for signaling, energy conversion systems for transport, and stability sensors for conformational editing. We seek to define the energy transduction events converting various stimuli into protein motion and to determine the structure of end point states. Spin labeling also allows analysis of well-defined biochemical intermediates in native-like environments without the conformational selectivity imposed by lattice forces.

Current topics of interests include:

Molecular aspects of protein aggregation in aging and disease: Structure and function of heat shock proteins, structure of amyloids.

Multidrug resistance in cancer and infectious diseases: Structural basis of substrate recognition and translocation for the bacterial lipid flippase MsbA, human multidrug resistance protein (p-glycoprotein) and the bacterial multidrug transporter EmrE.

Neurotransmitter transporters: Dissection of the transport cycle for bacterial homologs of the dopamine and serotonin transporters in collaboration with the Jonathan Javitch lab at Columbia University.

CamKII Kinase: Structural basis of regulation and motifs of protein-protein interactions in collaboration with the Roger Colbran Lab at Vanderbilt University.