Personalized Structural Biology

Personalized Structural Biology

Medicine has experienced a revolution in the methods used to diagnose and treat disease. Dramatic reductions in the cost of DNA sequencing are enabling clinicians to leverage the full genome sequence of patients to inform diagnosis and treatment. This genetic information offers the promise of targeted, personalized treatments that reflect patients’ genetic backgrounds and predispositions to disease. However, interpreting the clinical relevance of any variant observed in an individual’s genome is not a straightforward task, and represents a significant challenge in translating genomic information to improvements in clinical outcomes.

The fundamental concept of Personalized Structural Biology (PSB) is that amino acid coding variants that are distant in the linear sequence of the genome, may nevertheless interact within the three-dimensional context of the folded protein. In other words, the “functional” consequence of any coding variants should be evaluated within the context of the protein structure.

The core PSB concept is made feasible because like genomics, the field of protein structural biology has been revolutionized over the past 20 years. Thanks to advances in crystallography, cryoEM and artificial intelligence, we now have three-dimensional structures or models for hundreds-of-thousands of proteins (over 10 times as many as 20 years ago). Thus, we can readily contextualize the vast majority of human protein coding variants in 3-dimensional space.