Nicholas Polizzi, Assistant Professor, Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Dana Farber Cancer Institute, will give a talk titled, "Designing ligand-binding proteins from scratch"

ABSTRACT

Most proteins function by first binding a ligand, such as another protein, peptide, or small molecule. The Polizzi laboratory aims to learn the rules of protein–ligand binding through the lens of de novo protein design. In de novo design, a protein’s structure and sequence are computed from first principles. This approach has seen much recent success for the creation of new protein shapes. However, the design of proteins that bind to specific ligands remains an outstanding challenge. In this talk, I will discuss our lab’s approach to designing small-molecule-binding proteins from scratch. By analyzing thousands of protein structures in the Protein Data Bank, we discovered a structural “code” used by proteins to preferentially bind the chemical groups commonly found in small molecules. We developed a design algorithm called COMBS that uses the structural code to create custom ligand-binding sites; and we demonstrated its utility through the design of a de novo protein that specifically binds the antithrombotic drug, apixaban. This work sets the stage for building bespoke ligand-binding proteins with many potential applications in biology and medicine.