Advances in DNA sequencing and machine learning are illuminating protein sequences and structures on an enormous scale. However, the energetics driving folding are invisible in these structures and remain largely unknown. The hidden thermodynamics of folding can drive disease, shape protein evolution, and guide protein engineering, and new approaches are needed to reveal these thermodynamics for every sequence and structure.
 

In this webinar, Dr. Kotaro Tsuboyama presented on cDNA display proteolysis, a new method for measuring thermodynamic folding stability for up to 900,000 protein domains in a one-week experiment. Using this immense dataset, they quantified (1) environmental factors influencing amino acid fitness, (2) the global divergence between evolutionary amino acid usage and protein folding stability and (3) thermodynamic couplings (including unexpected interactions) between protein sites.