A spin-1 representation for dual-funnel energy landscapes
The interconversion between the left- and right-handed helical folds of a polypeptide defines a dual-funneled free energy landscape. In this context, the funnel minima are connected through a continuum of unfolded conformations, evocative of the classical helix-coil transition. Physical intuition and recent conjectures suggest that this landscape can be mapped by assigning a left- or right-handed helical state to each residue. In this study, we explore this possibility using all-atom replica exchange molecular dynamics and an Ising-like model, demonstrating that the energy landscape architecture is at odds with a two-state picture. A three-state model—left, right, and unstructured—can account for most key intermediates during chiral interconversion. Additionally, competing folds and excited conformational states still impose limitations on the scope of this approach. However, the improvement is stark: Moving from a two-state to a three-state model decreases the fit error from 1.6 k B T to 0.3 k B T along the left-to-right interconversion pathway.