De Novo Design of Functional Proteins

Lipid De novo protein design involves the creation of proteins from scratch, rather than by modification of natural proteins. A variety of functionally rich proteins have been achieved. Some functions, such as binding to protein interfaces have been relatively easy, because the interactions that stabilize interfaces are also used to stabilize the folded structures of proteins, and available computational methods have been well calibrated to this task. It has been more difficult to design functions that involve molecular recognition of small, polar molecules or dynamic processes. I will describe recent progress in the design of proteins that bind small molecules, and the use of these proteins in potential biomedical applications such as drug targeting, delivery and as drug reversal agents. We also have made progress in the area of the design of proteins with enzymatic activities, including ones that catalyze reactions at rates that exceed most natural enzymes. We also have designed proteins that catalyze reactions for which there were no known protein catalysts.

A second challenging area of interest in de novo protein design has been the construction of useful membrane proteins. I will describe the design of semisynthetic membrane proteins that function as ion channels, and their application to DNA and RNA sequencing. The talk will also demonstrate how de novo design can be used to test the mechanisms by which protons are conducted with high specificity and efficiency through transmembrane proton channels.