INTERNAL MOTIONS OF CARBOHYDRATES AS PROBED BY COMPARATIVE MOLECULAR MODELING AND NUCLEAR-MAGNETIC-RESONANCE OF ETHYL BETA-LACTOSIDE

The realization that conformational flexibility must be incorporated i nto the description of the structural and dynamical behavior of carboh ydrates has stimulated the quest for an appropriate force field and as sociated parameterization capable of dealing with the many specific fe atures of these molecules. Accordingly, we set out to evaluate the cap acity of very different force fields to reproduce a series of experime ntal spectral data such as optical rotatory dispersion, coupling const ants, and nuclear Overhauser effects. NOESY volumes and long-range hom onuclear and heteronuclear vicinal coupling constants were measured at 400.13 MHz. Optical rotation measurements were also performed on ethy l beta-lactoside. The conformational behavior of ethyl beta-lactoside was investigated in three different molecular mechanics force fields l eading to three complete ensembles of theoretical conformations, which were used for evaluating these statistically averaged observables. Th e calculations of optical rotation followed a recent model based on in teracting oscillators. Coupling constants were calculated using the ap propriate sets of Karplus-type equations, and theoretical nuclear magn etic resonance (NMR) relaxation data were obtained for models which ac count for either slow or fast internal motions. The calculated potenti al energy surfaces were shown to be dependent on the type of force fie ld, even in the case of such a simple disaccharide. They differ in sev eral respects, including the number and location of low-energy conform ers and the shallowness of the dominant primary region. It was possibl e to assess the different time-averaged orientations about the glycosi dic linkage of the three force fields from the fit obtained for the in terglycosidic heteronuclear coupling constants. Poor fits between theo retical and experimental NOESY volumes were observed for all three for ce fields when the slow internal motion model was used, while a greatl y improved fit was obtained when the fast internal motions model was a pplied. It has been shown that the motional model established from NOE SY data is analogous to the one obtained from molecular dynamics simul ations. The quality of the fit for the NOESY data varies with the forc e fields and corroborates the classification obtained from heteronucle ar coupling. (C) 1995 by John Wiley & Sons, Inc.