We are interested in protein-protein interactions and the ways in which the affinity and specificity of such interactions can be manipulated. Our studies include computational and experimental approaches, ranging from the atomic design and characterization of novel binding modules to the re-wiring of cellular pathways. We also do work to develop novel biomaterials and in vivo imaging techniques.
Stimulus Responsive Bionanomaterials
Stimulus-responsive hydrogels are promising vehicles for the controlled delivery of small molecules, cells, and other molecular cargo to specific sites in the body. We take advantage of the modularity, specificity, and tunability of non-covalent tetratricopeptide repeat (TPR) protein-peptide interactions to create such hydrogels. Small molecules and proteins are encapsulated upon mixing of TPR protein and peptide components and subsequently released in response to changes in pH and ionic strength. We are investigating how the atomic detail of the TPR protein-peptide interactions translate to the macroscopic properties of the hydrogels, namely viscoelasticity and stimuli-responsiveness.
Novel Hsp90 Inhibitors as Potential Anti-Cancer Agents
Unregulated cellular proliferation caused by mutation or dysregulation of growth-promoting proteins is an underlying cause of many cancers. Many growth-promoting proteins, including Her2, are clients of the chaperone Hsp90, whose activity promotes correct folding and maturation of the clients. We have identified small molecules that kill cancer cells and inhibit Hsp90 activity by disrupting its interaction with an essential co-chaperone. We are currently investigating the molecular and cellular mechanism of action of these compounds. More generally, we are investigating the balance between folding and ubiquitylation of Hsp90 client proteins and ways in which this balance can be perturbed.
Designed Proteins as Novel Imaging Reagents
Functionalized Microcapsules and Surfaces
We are interested in the creation of self-assembling materials made from modular protein building blocks, most notably the SpyTag/SpyCatcher pair. SpyTag is a 13-residue peptide sequence and SpyCatcher is a 12 kDa protein that interact to form a covalent isopeptide bond. Strategic placement of SpyTag/SpyCatcher in our constructs has enabled us to design proteins that interact in a robust, specific way to create our desired materials. Another building block of particular interest to us is a bacterial hydrophobin, BslA, that forms a stable monolayer at both air/water and water/oil interfaces. We have created protein constructs with the SpyTag sequence both at the N-terminus and the C-terminus of BslA for use in decorating surfaces and microcapsules with proteins of interest attached to SpyCatcher. In collaboration with the Yan, Osuji, and Batista labs at Yale, we have demonstrated the construction of readily functionalizable microscapsules with potential applications in drug delivery. In the future, we are looking to use similar design techniques to decorate micropatterned surfaces.