Threading or Tumbling? Insight into the Self-Inclusion Mechanism of an altro-α-Cyclodextrin Derivative

Abstract

An altro-α-cyclodextrin (altro-α-CD) derivative bearing an adamantyl end group can form a pseudo[1]rotaxane through the self-inclusion of its arm into the CD cavity. Yet, how the bulky end group translocates from the secondary side of the altro-α-CD to its primary side to form the pseudo[1]rotaxane remains somewhat unclear. In the present work, the atomic-level mechanism that underlies the formation of the self-inclusion complex was investigated by means of molecular dynamics simulations combined with microsecond time scale free-energy calculations. Two possible transition pathways leading to the formation of the same self-inclusion structure were considered, namely, threading of the adamantyl group through the altro-α-CD cavity, and tumbling of the altropyranose unit of altro-α-CD. The free-energy profiles characterizing the threading and the tumbling pathways were determined, revealing in each case the free-energy barrier. For the former pathway, the free-energy barrier with respect to the unbound state amounts to 53.6 kcal/mol, unphysically high to make the threading route feasible. Conversely, for the latter pathway, a 16.0 kcal/mol free-energy barrier is measured, indicating that the formation of the pseudo[1]rotaxane may result from the tumbling of the altropyranose unit bearing the adamantyl arm.