Labeling Rare and Transient Conformations on the Landscape

The amino acid sequence of a protein encodes more than the native three-dimensional structure; it encodes the entire energy landscape – an ensemble of conformations whose energetics and dynamics are finely tuned for folding, binding and activity. Small variations in the sequence and environment modulate this landscape and can have effects that range from undetectable to pathological, even when the protein's folded structure is unchanged. I will describe results from different experimental approaches that have allowed us to selectively label rare and transient conformations and peak into these hidden regions of the energy landscape and investigate their importance in protein folding and the SARS- CoV-2 Spike protein.