Protein design for cyclic peptide and small molecule binding

Abstract

Proteins can bind diverse classes of ligands and the presence of these ligands can induce a response in the cell. Particularly, for the design of systems where the interaction of a ligand with intracellular binding partners can elicit a response, the ligand must be able to cross the cell membrane. To achieve this aim, I explored two classes of ligand: cyclic peptides and small molecule HIV protease inhibitors. I designed protein binders for each of these ligand classes. For one cyclic peptide, I utilized a library of designed homodimeric scaffold proteins as the protein binding component and demonstrated their response to the cyclic peptide in mammalian cells. For HIV protease ligands, I explored the application of deep learning based protein design tools to generate backbones, design sequences and predict the ligand-protein complex. While two libraries of designs were screened for binding via yeast display with a biotinylated ligand, further development of the design pipeline is necessary to obtain protein binders with high affinity to these ligands.