(6ga) Design of Genetically Encodable Protein Switches and Potent Metallobiocatalysts

Precise molecular recognition between proteins and small molecules is critical to cellular function. A rigorous test of our understanding of the physiochemical principles that govern molecular interaction phenomena is the creation of de novo protein-ligand interfaces with programmable properties. I recently developed a generalizable computational/experimental hybrid method for designing proteins that bind small molecules and used it to create selective binders for the steroid digoxigenin. This work and other exciting advances provide a platform for creating novel ligand binding proteins, but fundamental gaps in our understanding of structure-function relationships in proteins need to be addressed in order to robustly and routinely design molecular biodevices that sense the presence of the bound small molecule and respond by performing a specified function. The goal of my interdisciplinary research group will be to uncover the design principles necessary to develop next-generation systems-level protein technologies in which molecular recognition events are coupled with downstream biological or chemical functionalities. Design advancements will be motivated by and provide insight into the biochemical/biophysical principles that promote allosteric changes in proteins and/or enable the coordinated integration of multiple complex chemical events. In particular, we will focus on two major avenues: designing novel molecular switches for regulating metabolic pathways, and developing new metallobiocatalysts for challenging small molecule activation reactions related to green chemistry and energy. Through our design efforts, we hope not only to create novel functional biomolecules but also to uncover design principles that shed light on the underlying structure-function relationships and regulatory mechanisms in natural systems.