William "Bill" DeGrado
University of California, San Francisco
De Novo Protein Design of Functional Proteins
SESSION 12: NEW FRONTIERS IN COMPUTATIONAL PEPTIDE DESIGN PART 1
Thursday, June 29, 2023, at 08:30 am - 08:55 am
Not too long ago, the design of proteins from scratch that fold into predictable structure was considered an impossible task, but it is now increasing routine. Given our ability to design proteins structures the next challenge has been to design function. The success or failures of the designs informs our understanding of the principles underlying the desired function and additionally provides the first step towards design of proteins with useful functions not available to natural proteins.
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 methods for the design of proteins that bind small molecules, and the use of these proteins in potential biomedical applications such as drug delivery and as drug reversal agents.
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 protein that function as ion channels, and their application to DNA and RNA sequencing. The talk will also 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.
One research interest is in the de novo design, in which one designs proteins or drugs beginning from first principles. This approach critically tests our understanding of protein folding and function, while also laying the groundwork for the design of molecules with properties unprecedented in nature.