We study the dynamical process of membrane protein folding.
Nearly one third of open reading frames encode proteins that live in membranes. These membrane proteins are essential for many biological functions including ion transport, molecular sorting, energy transduction, bacterial pathogenesis, and cell signaling. Over half of the drugs on the market today are thought to target membrane proteins, emphasizing their medical importance. Paradoxically, very little is known about how membrane proteins attain their native folds and how membrane proteins assemble into molecular complexes.
Research in my laboratory addresses fundamental biological questions concerning the formation of native structures in membrane proteins:
How does the sequence for a membrane protein specify the fold?
What are the physical principles dictating membrane protein folding and interactions?
What is the role of the lipid bilayer environment?
What principles for protein folding are similar between soluble and membrane proteins?
To address these questions our research efforts are focused on developing a physical understanding of membrane proteins, their folding and interactions, their specificity, their stability, their regulation, and their evolution. We carry out experiments that probe the chemistry of both helical and beta-barrel transmembrane proteins.
Our tools include an array of biophysical methods (analytical ultracentrifugation, light scattering, fluorescence spectroscopy, circular dichroism) as well as complementary molecular dynamics calculations. Through these biophysical studies on a variety of membrane proteins with a diversity of folds we aim to elucidate governing principles for membrane protein folding and interactions.
Our most recent work has resulted in a novel hydrophobicity scale that describes the free energy of transfer of amino acid side chains from water to the bilayer in the context of a natively folded protein. We are currently determining the bilayer-depth dependence of these free energy changes, and we are exploring the generality of our results by experiments on a variety of different membrane proteins.
We are also interested in membrane protein folding kinetics and how membrane proteins are able to insert and fold into membranes and use biophysical tools to investigate folding time courses and conformations and the influences that cellular chaperones have on the kinetic pathways of membrane protein folding.