Research

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, including metals, can alter the thermodynamic landscapes of proteins. These changes can result in diseases such as neurodegeneration and cancer.

Studies such as deep mutational scanning explain some mechanisms behind these conformational changes. However, we still cannot predict, engineer, or therapeutically alter these changes beyond a subset of well-studied systems. Our lab addresses these problems through two separate but parallel approaches.

One arm of the lab develops methods for protein conformational modeling. We combine cryo-EM, physics-based simulation, and deep learning to predict protein flexibility and energetics more robustly and accurately. The second arm applies our methods alongside existing methods to tune the energetics of de novo designed proteins. Our goal is to create 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.