The Vanderbilt Program in Personalized Structural Biology (PSB) collaborates extensively with the Vanderbilt Ingram Cancer Center (VICC) and other leading institutions to characterize variants of unknown significance (VUS) in cancer patients. Over the last decade, the coming-of-age of protein structure prediction has made it possible to create high-quality atomic structural models of proteins for which there are no known experimental structures. The PSB uses a combination of Rosetta1 and modern deep learning methodologies2,3 to build models of proteins with VUS. Subsequently, we run Rosetta energy calculations and molecular dynamics (MD) simulations of the protein models to make predictions about the effects of the VUS mutations on function and/or resistance to medical therapy4–9. The PSB is unique because of its organic relationship with practicing physicians and physician-scientists. We actively engage in formal and informal dialogues with our friends and colleagues in the clinics to make structural analysis of protein mutations a common and important component of clinical decision-making. As we and others continue to advance the technology to efficiently and comprehensively evaluate VUS, it is our vision that such analyses will become a routine component of modern health care delivery.

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