Thinking Outside the Lattice
The fundamental question of interest to our lab is that of protein allostery: how do distant parts of a protein communicate in order to tune function and perform sequential steps in the correct order? Our lab is approaching this problem from multiple angles. We are best known for our unique use of X-ray scattering and diffraction, but we also employ cryo-electron microscopy (cryo-EM) and other biophysical methods. We work on four areas within the theme of “proteins in motion”.
[ Evolution of Enzyme Allostery ]
We study the diversity and evolution of allosteric mechanisms in enzyme families. By using small-angle X-ray scattering (SAXS) and mathematical decomposition techniques, we can map the conformational landscape of complex allosteric enzymes in solution. This information in turn allows us to determine structures by cryo-electron microscopy (cryo-EM) and crystallography that provide detailed insight into allosteric mechanisms. The evolution of allostery is of fundamental interest to us because it provides a powerful window into the relationship between protein sequence, structure, function, and dynamics.
[ Protein Correlated Motions ]
Conventional crystallography involves analyzing sharp diffraction patterns, commonly called Bragg data. However, real crystals are not perfectly periodic and produce additional scattering between the Bragg peaks. This smooth background pattern, known as diffuse scattering, contains information about correlated displacements within the crystal. We are developing robust methods for collecting, processing, and analyzing diffuse scattering data from protein crystals that we ultimately will use to learn about correlated protein motions that underlie protein allostery.
[ Flexible Enzymes ]
Many enzymes of pharmaceutical interest are highly flexible or undergo significant domain rearrangements during catalysis. Such enzymes are often too dynamic to be captured by conventional crystallography. Although small-angle X-ray scattering (SAXS) is not limited to proteins that are relatively rigid, it yields low-resolution data that is underdetermined relative to the many conformational degrees of freedom of flexible enzymes. We are interested in combining SAXS with other biophysical methods to solve such problems.
[ Complex Metalloenzymes ]
As a lab, we are interested in understanding how life evolves and adapts to unusual environments. In particular, we have a fascination with the evolutionary significance of metalloenzymes, proteins that use metal-containing cofactors to perform challenging - and often ancient - chemistry. We are using various advanced structural methods to characterize catalytically relevant conformational changes in metalloenzymes.