Biophysical Approaches for Engineering Functional Proteins

We take inspiration from Nature to build new proteins that guide our understanding of how natural proteins function: we can distill complex natural proteins into simple model systems where we have exact control over the physicochemical properties of the entire system. Our group combines protein design principles with biophysical approaches to 1) test mechanistic hypotheses of membrane protein structure and function, and 2) define novel protein-protein interactions for engineering protein-based therapeutics.

Proton-Coupled Channels and Transporters

Proton transport mechanisms play critical roles in bioenergetic and biocatalytic processes. A key question is: how do protons, the smallest ions, precisely move across cellular membranes? Through protein design, we can dissect how proton channels use distinct structural features in directing proton movement at a fundamental level. We can then couple our knowledge of transport to build minimalist proton-selective channels and begin to design more complex proton-coupled transport proteins.

Water-Conducting Channels

Do we understand water selectivity and conductivity in natural channels, like aquaporins, on a biophysical basis? Can we engineer minimalist, water-selective channels? This work explores key questions in water selectivity and conduction rates through protein design. We test ideas of hydrogen-bonded networks in defining water selectivity to understand water conductivity at the atomic level.

Design of Protein-Protein Interactions for Therapeutics

Immune responses require many different protein-protein interactions (PPIs). These PPIs enable the immune system to distinguish between self/non-self and to neutralize invading pathogens. We are interested in understanding these PPIs on a molecular level in order to engineer novel protein-binders that sequester and neutralize pathogens or prevent autoimmune responses.

Tools of the Trade

To address all these biophysical questions, we use an array of computational and experimental techniques! On the computational side, we use a lot of software developed for protein design and for molecular dynamics simulations. On the experimental side, we do everything from peptide synthesis to protein expression, ITC, SPR, BLI, high throughput assay development, and X-ray crystallography, to name a few. We are also open to bringing new techniques into the lab and doing whatever it takes to answer our scientific questions!