Hysteresis as a Marker for Complex, Overlapping Landscapes in Proteins

Topologically complex proteins fold by multiple routes as a result of hard-to-fold regions of the proteins. Oftentimes, these regions are introduced into the protein scaffold for function and increase frustration in the otherwise smooth-funneled landscape. Interestingly, while functional regions add complexity to folding landscapes, they may also contribute to a unique behavior referred to as hysteresis. 'While hysteresis is predicted to be rare, it is observed in various proteins, including proteins containing a unique peptide cyclization to form a fluorescent chromophore as well as proteins containing a knotted topology in their native fold. Here, hysteresis is demonstrated to be a consequence of the decoupling of unfolding events from the isomerization or hula-twist of a chromophore in one protein and the untying of the knot in a second protein system. The question now is can hysteresis be a marker for the interplay of landscapes where complex folding and functional regions overlap?