Mechanistic and dynamic insights into ligand encapsulation by helical arylamide foldamers

Molecular capsules have been extensively used in catalysis, drug delivery, molecular recognition and protection of ligands from degradation. Novel "apple peel" shaped helical arylamide capsules have been experimentally pursued due to their flexible nature and designability. They were found to encapsulate a variety of small molecules. The apple peel shape of the capsules led to a hypothesis that binding and release of ligands involve partial unfolding. However, the exact mechanism is unknown. Using molecular dynamics simulations with our new aryl-amide force field parameters, we identify two low energy barrier binding/release mechanisms, in which the capsule's helical structure is either minimally disturbed or restored quickly (within 100 ps). Furthermore, we determine the effects of ligand sizes, their chemical nature (hydrogen bonding capabilities), and solvents on binding modes and stabilities. Our findings not only support experimental observations but also provide underlying principles that allow for rational design of foldamer capsules.