Helix handedness inversion in arylamide foldamers: elucidation and free energy profile of a hopping mechanism.

We report the first atomistic level description of the handedness inversion mechanism for helical arylamide foldamers. The key process in the handedness inversion is the simultaneous unfolding and folding of two adjacent aryl-aryl linkages, propagating from a helix terminus along the strand. Intermediates along the inversion pathway have a common feature - a single unfolded aryl-aryl linkage (through C(aryl)-C(amide) rotation) connecting two helical segments of opposite handedness. This explicit solvent metadynamics study also provides thorough quantitative free energy information for each step of the previously uncharacterized inversion pathway.