UCSF

The ability of proteins to recognize and bind small molecules underlies numerous biological processes and has broad applications in biotechnology and medicine. In this dissertation, I investigate the de novo design of proteins that recognize chemically complex small molecules. Chapter 1 introduces the principles of molecular recognition and de novo protein design that motivate this work. Chapter 2 describes the computational design, experimental optimization, and structural validation of de novo proteins that bind the anthracycline chemotherapeutic doxorubicin, resulting in a compact 85-residue protein with nanomolar affinity and a novel protein fold. Chapter 3 explores the translational potential of these proteins through engineering of an albumin-binding fusion that preserves doxorubicin binding while introducing recognition of human serum albumin. Together, these studies demonstrate that de novo protein design can create structurally novel proteins with programmable molecular recognition and establish a foundation for future therapeutic and biotechnological applications.