CONFORMATION OF THE OLIGOSACCHARIDE RECEPTOR FOR E-SELECTIN

A tetrasaccharide related to the blood group oligosaccharides, known a s sialyl Lewis(X), has been proposed as the receptor for the lectin re sponsible for leukocyte adhesion named alternatively as E-selectin or ELAM-1. The C-13- and H-1-nmr spectra have been completely assigned fo r a tetrasaccharide model of this receptor, Neu5Ac alpha- (2 --> 3)-Ga l beta-(1 --> 4) -[Fuc alpha- (1 --> 3) -] GlcNAc beta-NHAc. Quantitat ive nuclear Overhauser data (NOESY) have been recorded and analyzed by a complete spin matrix simulation method. Conformational space was ex haustively searched and all conformational models whose simulated NOES Y spectra matched the experiment were found. Molecular mechanics and m olecular dynamics calculations were carried out to test whether the ex perimental conformations are low energy and thus likely to represent t rue single conformations for the tetrasaccharide. It was concluded tha t while the Lewis' trisaccharide portion of the compound adopts a sing le conformation, there is likely to be some flexibility about the Neu5 Ac alpha- (2 --> 3) -linkage. A model featuring fast exchange between two different conformations of this linkage is found to be consistent with both the nmr experiments and the molecular dynamics simulations. (C) 1994 John Wiley & Sons, Inc.