Molecular recognition in cyclodextrin complexes of amino acid derivatives.1. Crystallographic studies of beta-cyclodextrin complexes with N-acetyl-L-phenylalanine methyl ester and N-acetyl-L-phenylalanine amide pseudopeptides

Cyclodextrins (CDs) are widely utilized in studies of chiral and molecular recognition. By changing the functionality of the guest molecule, the effec t of such changes on recognition by the host CD molecule can be examined. W e report crystal structure determinations for two nearly isomorphous comple xes of phenylalanine derivatives: beta -CD/N-acetyl-L-phenylalanine methyl ester and beta -CD/N-acetyl-L-phenylalanine amide. The complexes crystalliz e as hydrated head-to-head host dimers with two included guest molecules in space group P1. The crystal packing is such that it presents a nonconstrai ning hydrophobic pocket adjacent to a hydrophilic region, where potential h ydrogen-bonding interactions with hydroxyl groups of neighboring cyclodextr in molecules and waters of hydration can occur. The two host molecules disp lay very similar conformations; only a few of the primary hydroxyl groups a re con formational ly disordered. There are a number of changes in the loca tion of water of hydration molecules, some of which are the result of diffe rent hydrogen-bonding interactions. For the different guest molecules, simi lar modes of penetration are observed in the CD torus, however, there is a 0.985-Angstrom shift in the position of the guest molecules in the host tor us, which takes place without changing the hydrophobic interactions display ed by the phenyl side chains. This observation and the thermal motion of th e guest molecules in the ester complex are taken as evidence that complex b inding forces are weak. The pseudopeptides experience a significant degree of flexibility in the crystalline environment provided by CD dimers. Confor mational differences of the pseudopeptide backbones and the presence of dis ordered water molecules in the host-guest interface provide examples of dif ferent hydrogen-bonding schemes of similar potential energy. The crystal sy stem presents an opportunity to establish a database of molecular interacti ons for small peptides and peptide analogues with waters of hydration and f unctional groups in nonconstraining binding environments.