Hysteresis as a Marker for Complex, Overlapping Landscapes in Proteins

Abstract

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?

Differential Contribution of Tryptophans to the Folding and Stability of the Attachment Invasion Locus Transmembrane β-Barrel from Yersinia pestis

“…In GdnHCl, although (un)folding can be achieved in various LDAO concentrations, the equilibrium unfolding experiments demonstrate hysteresis within experimental time frames, which is not uncommon for TM β-barrels101115, and suggests the existence of alternate folding and unfolding pathways and/or dissimilar activation energy values in the two processes. Using Trp fluorescence (Fig.…”

A knot in the protein structure – probing the near‐infrared fluorescent protein iRFP designed from a bacterial phytochrome

“…A hysteretic behavior of the unfolding–refolding curves was recently observed for 1O6D RNA methyltransferase. This behavior was explained by the decoupling of the unfolding events from the untying of the knotted polypeptide chain [67]. Thus, a non-hysteretic behavior of the unfolding–refolding curves of iRFP in apoform can be indicative of the lack of deep traps in the folding pathway of this protein.…”

Noise-induced transitions in rugged energy landscapes

“…This scenario is very much analogous to the model described in (23) and (25), where the parameter α controls the strength of an external perturbation, and for which hysteresis occurs only where the noise intensity σ is below a critical threshold. More generally, the observation that roughness of the energy landscape can give rise to hysteresis effects has been observed in various systems, for example hysteresis of contact angles at the solid-liquid interface of fluids wetting rough surfaces [16,18,20,49], hysteresis in loading and unloading of rough adhesive surfaces [50], as well as folding-unfolding hysteresis in proteins with complex energy landscapes [51].…”