PARAMETRIZATION AND APPLICATION OF CHEAT95, AN EXTENDED ATOM FORCE-FIELD FOR HYDRATED (OLIGO)SACCHARIDES

completely revised version of the CHEAT force field (carbohydrate hydroxyl groups represented by extended atoms) is presented. This force field is meant to allow simulation of oligosaccharides in aqueous solution without the explicit inclusion of water molecules. Thus, the average effect of intra- and intermolecular hydrogen bonding has been introduced into the potential energy function by adding a new (extended) atom type to the Quanta/CHARMm 4.0 force field. The additional force field parameters for the new atom type have been optimized by using a set of 56 estimated interaction energy differences for solvated cyclohexanols and aldopyranoses. The resulting CHEAT95 force field, which is computationally very efficient, has been applied to the disaccharides cellobiose, maltose, and sucrose. By comparing calculated potential energy maps with experimentally determined conformational data from X-ray, NMR, and optical rotation studies, it is shown that CHEAT95 results closely agree with the disaccharide conformations observed in solution. All but one conformation of the disaccharides in crystal structures are within 4 kcal/mol of the calculated global minima. In particular sucrose, which conformational behavior constitutes a major problem to force field calculations, could be simulated in full agreement with the experimental data. Finally, a complete conformational search has been carried out for the glycosidic and exocyclic dihedrals of GlcNAc beta(1-->4)[Fuc alpha(1-->3)]GlcNAc beta, a structural variant of Lewis X. The CHEAT95 results are in better agreement with NMR data and molecular dynamics simulations that explicitly include water molecules rather than with in vacuo calculations.