Internal motions of carbohydrates as probed by comparative molecular modeling and nuclear magnetic resonance of ethyl β‐lactoside

The realization that conformational flexibility must be incorporated into the description of the structural and dynamical behavior of carbohydrates has stimulated the quest for an appropriate force field and associated parameterization capable of dealing with the many specific features of these molecules. Accordingly, we set out to evaluate the capacity of very different force fields to reproduce a series of experimental spectral data such as optical rotatory dispersion, coupling constants, and nuclear Overhauser effects. NOESY volumes and long‐range homonuclear and heteronuclear vicinal coupling constants were measured at 400.13 MHz. Optical rotation measurements were also performed on ethyl β‐lactoside. The conformational behavior of ethyl β‐lactoside was investigated in three different molecular mechanics force fields leading to three complete ensembles of theoretical conformations, which were used for evaluating these statistically averaged observables. The calculations of optical rotation followed a recent model based on interacting oscillators. Coupling constants were calculated using the appropriate sets of Karplus‐type equations, and theoretical nuclear magnetic resonance (NMR) relaxation data were obtained for models which account for either slow or fast internal motions. The calculated potential energy surfaces were shown to be dependent on the type of force field, even in the case of such a simple disaccharide. They differ in several respects, including the number and location of low‐energy conformers and the shallowness of the dominant primary region. It was possible to assess the different time‐averaged orientations about the glycosidic linkage of the three force fields from the fit obtained for the interglycosidic heteronuclear coupling constants. Poor fits between theoretical and experimental NOESY volumes were observed for all three force fields when the slow internal motion model was used, while a greatly improved fit was obtained when the fast internal motions model was applied. It has been shown that the motional model established from NOESY data is analogous to the one obtained from molecular dynamics simulations. The quality of the fit for the NOESY data varies with the force fields and corroborates the classification obtained from heteronuclear coupling. © 1995 by John Wiley & Sons, Inc.