“Synthetic Biology Approach to New-to-Nature Natural Products”

Dr. James Fraser

University of California San Francisco, Department of Bioengineering and Therapeutic Sciences

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Abstract: In a post-“structure prediction is solved” world, our lab is obsessed with the concept of statistical structural biology. We collect large datasets (X-ray fragment screens from 1000s of individual crystals) and use new statistical approaches to identify small molecule binders. This inspires new inhibitors, allosteric modulators, and enzyme design strategies. We also examine how experimental information encodes statistical distributions of conformations. This inspires software (e.g. qFit) that reveals hidden conformations, new guidance frameworks for diffusion models that reveals memorization, and experiments to extract even more information. These two aspects are synergistic in examining many aspects of biology. A current focus is the promiscuity of ligand binding in drug metabolism proteins, as part of the OpenADMET.