Using bright X-rays from the Department of Energy’s SLAC National Accelerator Laboratory and Lawrence Berkeley National Laboratory (Berkeley Lab), researchers pioneered an innovative approach to designing proteins with targeted functions. Their method generated new insights that allowed the team to turn a single designed protein into two new proteins with completely different functions—one of which is the most active designed enzyme to date.

In the study, published in Nature Chemistry, the University of California, San Francisco (UCSF), team for the first time combined X-ray studies of how small molecule fragments bind to designed proteins, known as crystallographic fragment screening, with a method used to design proteins, called directed evolution. This breakthrough approach could lead to simpler ways to improve enzymes and medications, among other uses.

“Our novel protein design strategy simultaneously explores the landscapes of chemical space and sequence space, which helps design functional proteins rapidly,” said Sagar Bhattacharya, postdoctoral researcher at UCSF and an author on the paper. “Instead of the typical 5–10 rounds or more of directed evolution, we achieved the 10-fold higher enzyme activity with just two rounds of directed evolution.”