“Design of Molecular Mechanics Modeling Techniques For Exploring Molecular Recognition Using Cyclodextrins.

Molecular mechanics modeling techniques have been developed to study the behavior of cyclodextrins (CDs) in capillary electrophoresis (CE) separations. Using the commercial computational package, Sybyl, the mechanisms of molecular recognition between organic analytes and CDs are investigated.

Cyclodextrin-modified capillary electrochromatography (CDCE) experiments were conducted to separate neutral derivitized naphthalene solutes using carboxymethyl-beta-cyclodextrin (CM-b-CD). Grid conformation-searching programs were developed to explore the interaction space between CD and solute and to calculate their interaction energies using molecular mechanics. The interaction energies correlated remarkably well with the separation behavior. It was found that extensive minimization (more than 3000 iterations) was required at each of the docking positions to achieve the best agreement between computational and experimental distribution coefficients (K_d).

Molecular modeling techniques were also used to guide the development of a new charged cyclodextrin resolving agent, heptakis (6-O-carboxymethyl-2,3-dimethyl)-b-cyclodextrin (HDMCM-b-CD). Molecular computer aided design (MolCAD) analysis and docking techniques revealed that HDMCM-b-CD would be superior to commercially available CDs for forming inclusion complexes with the target naphthalene derivative analytes. Molecular modeling studies also showed that significant intermolecular CD-CD interactions can occur under certain conditions, explaining some anomalous experimental findings. Additionally, the grid conformation-searching modeling technique was applied to chiral CDCE separations of dansyl amino acids (AAs) to explain separation behavior and to investigate different CD-CD interactions.