Proteins are nature’s molecular machines, carrying out essential tasks throughout the body. But their structures, shaped by billions of years of evolution, aren’t always suited to the challenges of modern medicine. At the UCSF School of Pharmacy scientists William DeGrado, PhD, James Fraser, PhD, and Tanja Kortemme, PhD, are using AI and innovative experimental techniques to design entirely new proteins that could lead to more precise, effective treatments for disease. 

DeGrado, a professor in the Department of Pharmaceutical Chemistry, helped pioneer de novo protein design: building proteins from scratch rather than modifying those found in nature. His lab is pushing the field forward by designing artificial enzymes, which can catalyze chemical reactions. In collaboration with Fraser, an expert in protein structure and dynamics, DeGrado has helped create a highly efficient artificial enzyme, advancing the possibility of designing molecular tools that perform tasks natural proteins cannot. 

Fraser, chair of the Department of Bioengineering and Therapeutic Sciences, develops experimental methods to capture proteins in motion, revealing how they shift between different shapes and interact with other molecules. This work helps researchers understand how proteins function in living systems and verify whether AI-designed molecules behave as predicted. Such insights are essential for creating new therapeutics that can engage disease-related proteins whose critical features may appear only briefly as they move between states. 

Kortemme, who is vice dean of research at the school, is using AI to design proteins with more sophisticated control over their activity. Her lab aims to create molecules that can switch between active and inactive forms, respond to specific biological cues, and interact with targets that conventional drugs may struggle to reach.  

Together, the researchers’ work points toward a new generation of engineered medicines designed not just to bind their targets, but to respond dynamically to the body’s changing environment. Potential applications range from more selective cancer treatments to new approaches for addressing other diseases. 

Read the full story: https://magazine.ucsf.edu/our-future-medicines-will-toggle-hinge-and-slide