The Biophysics of Protein Design

Proteins serve as the primary means of an organism’s ability to sense and respond to its internal and external environment. To achieve this, proteins undergo thermodynamically accessible conformational changes that initiate biological processes downstream. Mutations and external stimuli like metals can alter the thermodynamic landscapes of proteins, which can result in a host of diseases like neurodegeneration and cancer. While some of the mechanisms of these conformational changes are understood through studies such as deep mutational scanning, it is not yet possible to predict, engineer or therapeutically alter these changes beyond a subset of well-studied systems. Our lab addresses these problems in two separate, but parallel approaches. One arm of the lab focuses on methods development for protein conformational modeling, utilizing cryo-EM, physics-based simulation, and deep learning to build more robust and accurate predictions of protein flexibility and energetics. The second arm of the lab utilizes our own methods along with existing methods to tune the energetics of de novo designed proteins with the goal of making functional, dynamic biosensors and biomaterials.

Facilities

The Bethel Lab maintains its own private cluster of hundreds of CPUs and GPUs for simulation, inference and training. We also have allocations of the Triton Shared Computing Cluster and the Expanse Supercomputer hosted at UCSD. Additionally, we are users of the Cryo-EM facility, the Thermo Fisher Sandbox, and the Janelia Cores hosted by Howard Hughes Medical Institute.