The true nature of rotary movements in rotaxanes

Disentangling the different movements observed in rotaxanes is critical to characterize their function as molecular and biological motors. How to achieve unidirectional rotation is an important question for successful construction of a highly efficient molecular motor. The motions within a rotaxane composed of a benzylic amide ring threaded on a fumaramide moiety were investigated employing atomistic molecular dynamics simulations. The free-energy profiles describing the rotational process of the ring about the thread were determined from multi-microsecond simulations. Comparing the theoretical free-energy barriers with their experimental counterpart, the syn-anti isomerization of the amide bond within the ring was ruled out. The free-energy barriers arise in fact from the disruption of hydrogen bonds between the ring and the thread. Transition path analysis reveals that complete description of the reaction coordinate requires another collective variable. The free-energy landscape spanned by the two variables characterizing the coupled rotational and shuttling processes of the ring in the rotaxane was mapped. The calculated free-energy barrier, amounting to 9.3 kcal mol^-1, agrees well with experiment. Further analysis shows that shuttling is coupled with the isomerization of the ring, which is not limited to a simplistic chair-to-chair transition. This work provides a cogent example that contrary to chemical intuition, molecular motion can result from complex, entangled movements requiring for their accurate description careful modeling of the underlying reaction coordinate. The methodology described here can be used to evaluate the different components of the multifaceted motion in rotaxanes, and constitutes a robust tool for the rational design of molecular machines.