Speaker: Doeke Hekstra, Assistant Professor of Moelcular and Cellular Biology, Harvard University
Title: Visualization of correlated motions underlying enzyme function
The conformational dynamics of proteins underlie key aspects of protein function, including ligand/substrate binding and release, catalysis, and allosteric control. Experimental access to these dynamics has remained a major hurdle. To address this, we are developing new crystallographic methods to perturb protein free energy landscapes and detect the resulting conformational changes in atomic detail. The guiding hypothesis underlying this work is that proteins, and enzymes in particular, have evolved to traverse a small number of distinct, thermally accessible excited states, and that therefore these motions can be experimentally probed with modest physical perturbation.
I will illustrate these methods and concepts using the enzyme dihydrofolate reductase–an essential and ubiquitous metabolic enzyme that has served as a long-standing model system for the role of dynamics in enzyme function. I will show that we can, indeed, detect motions which have mostly gone unnoticed so far but constitute an apparent switch between two catalytically important conformations. If time permits, I will briefly discuss the computational challenges encountered in integrating crystallographic methods and atomistic modeling.