Many proteins are sensitive to the chemical makeup of their surrounding solution
We develop methods to control solution composition in the test tube and in the cell
Our goal is to modify solution composition to control protein function in health and disease
Read more about the current projects in the lab below
How do cells sense physical changes?
Proteins have been known for decades to respond rapidly and efficienty to changes in their solution environment. Yet examples where the cell utilizes this inherent, physical ability are scarce. We have found several examples of proteins that display a phenotypic response to changes in the cell's solution environment, and aim to trace these back to the structural changes that are the underlying cause of the phenotype.
To achieve this aim, we develop microscopy methods that cause rapid changes to the cell's environment, and combine these with biophysical studies of proteins that respond to such changes.
Solution-based protein design
Most protein design approaches use mutations to alter the structure of well folded proteins. This limits the application of protein design: over 30% of the proteome is thought to be "floppy", lacking a specific native fold. In addition, mutations are difficult to incorporate in live cells.
We aim to control protein structure by changing solution composition. Solutions can cause the burial or exposure of protein surfaces through repulsive or attractive interactions with them.
Tuning the composition lets us target specific protein moieties for burial or exposure. A high-throughput approach to quantify solution composition lets us scan many solutions rapidly and assess their effect on proteins structure and activity. Coupled with novel methods to perturb and control the intracellular environment, we aim to create cellular solutions that inhibit or promote specific pathways.
Solutions in evolution
The solution composition of cells is intimately tied to the environment in which the organism lives. For example, organisms living in high salt environments have evolved intracellular environments that differ dramatically from those living in fresh water. The internal composition of cells is poorly characterized, in no small part because it can vary spatially and temporally - even in a single cell. We plan to understand how the intracellular solution has evolved by developing methods to quantify the intracellular environment, and examining the changes that occur throughout evolution to protein surfaces.