Molecular recognition in cyclodextrin complexes of amino acid derivatives.2. A new perturbation: The room-temperature crystallographic structure determination for the N-acetyl-p-methoxy-L-phenylalanine methyl ester/beta-cyclodextrin complex

Cyclodextrins (CDs) are cyclic oligosaccharides that encapsulate various sm all organic molecules, forming inclusion complexes. Because CD complexes ar e held together purely by noncovalent interactions, they function as excell ent models for the study of chiral and molecular recognition mechanisms. Re cently, room-temperature crystallographic studies of both the 2:2 N-acetyl- L-phenytalanine methyl ester/beta -CD and 2:2 N-acetyl-L-phenylalanine amid e/beta -CD complexes were reported. The effect of changes in carboxyl back- bone functional group on molecular recognition by the host CD molecule was examined for the nearly isomorphous supramolecular complexes. A new perturb ation of the system is now examined, specifically perturbation of the aroma tic side chain. We report a room-temperature crystal structure determinatio n for the 2:2 N-acetylp-methoxy-L-phenylalanine methyl ester/beta -CD inclu sion complex. The complex crystallizes isomorphously with the two previousl y reported examples in space group PI; the asymmetric unit consists of a hy drated head-to-head host dimer with two included guest molecules. The cryst al packing provides both a nonconstraining extended hydrophobic pocket and an adjacent hydrophilic region, where hydrogen-bonding interactions can pot entially occur with primary hydroxyl groups of neighboring CD molecules and waters of hydration. The rigid host molecules show no sign of conformation al disorder, and water of hydration molecules exhibit the same type of diso rder observed for the other two complexes, with a few significant differenc es in locations of water molecules in the hydrophilic region near guest mol ecules. There is evidence for modest disorder in the guest region of an ele ctron density map. In comparing this system with the two previously reporte d complexes of phenylalanine derivatives, it is found that the packing of t he guest molecules inside the torus of the CD changes upon substitution of a methoxy group at the para position of the aromatic phenyl ring. Backbone hydrogen-bonding interactions for the guest molecules with the CD primary h ydroxyls and waters also change. This structure determination is a new and revealing addition to a small but growing database of amino acid and peptid omimetic interactions with carbohydrates.