Ab Initio Study of Lowest-Energy Conformers of Lewis X (Le^x) Trisaccharide

Abstract

This paper presents the first ab initio conformational study of the Gal--1,4-[Fuc-R-1,3]-GlcNAc--OCH3 and Gal--1,4-[Fuc-R-1,3]-GlcNAc--OH trisaccharides (Lewis x) in the gas phase. Their lowest-energy conformers were selected first by the MM2*-SUMM conformational search technique. MM2* relative energies do not follow the same order for the two similar compounds. The molecular geometries and energies of the lowest-energy rotamers (7 of the acetal and 11 of the hemiacetal) were further analyzed at the HF/6-31G(d) level of theory. The ab initio method yields the same energetic order for the rotamers of the two molecules with considerably larger energetic differences for the first 7 rotamers: the MM2* method provides 0.3-0.5 kcal/mol, whereas the HF/6-31G(d) method provides 4.5 kcal/mol. In the most stable MM2* structures the hydrogen-bonded chains of galactose (in counterclockwise direction) and fucose (in clockwise direction) are not connected. The Gal(O6H) is a hydrogen bond donor (in clockwise direction) to the O3 glycosidic oxygen of GlcNAc. The Fuc(O2H)f(OdC)GlcNAc interaction connects the fucose and GlcNAc. In contrast, the most stable HF/6-31G(d) structure has a long chain of seven ordered hydrogen bonds including a Gal(O6H)f(O3)Fuc interaction (with clockwise hydrogen-bonded chain in galactose and fucose). The torsion angles for Fuc-R-1,3-GlcNAc and Gal--1,4-GlcNAc glycosidic bonds agree well in the solid, liquid, and gas phases. For example there is a rather good overlap between the GlcNAc moiety of one of the X-ray structures and the most similar HF/6-31G(d) structure. The stacking of the fucose and galactose moieties is similar. The orientations of the hydroxyl groups are usually different, as they are influenced by intramolecular hydrogen bonding in the gas-phase Hartree-Fock structure versus intermolecular hydrogen bonding in the solid-phase X-ray structure.

Ab Initio Conformational Study of Two Lewis X Analogues

“…7 Comparison of the torsion angles in Tables 2 and 4 shows that the HF/6-31G(d) and MM2* results agree with each other within few degrees for the first three rotamers. Similar qualitative agreement in the geometry was observed between the MM2* and HF/6-31G(d) results for Le x .…”

“…Other rotamers can occur in the interactions with receptors, but they have considerably higher energy in the gas phase. Figure 3 shows the distribution of the MM2* results for the 11 most stable rotamers of Le x , II, in the τ1 Fuc , τ3 GlcNAc , τ4 GlcNAc , and τ1 Gal conformational space from our earlier study 7 and the experimental results. The four different NOE NMR results are noted as + soln., E, P, and L for measurements in water solution, and when bound to E-, P-, and L-selectins, respectively.…”

“…7 Their constants are valid only for the small (<30°) ranges given in Table 1. These transformations allow us to use only the heavy atom C-C-O-C torsion angles to compare the solid-, liquid-, and gas-phase structures, avoiding the uncertainties arising from H atom positions in the X-ray measurements.…”

“…10,13 Due to the strong donor interaction with the oxygen atom of the NAc group the τ2 torsion angle for the second OH group of the fucose moiety deviates considerably from -60°in Le x . 7 In the analogues, this interaction is missing and τ2 is not far from (60°in some of the most stable rotamers (cf. Tables 2 and 3).…”

“…14 This is discussed in our previous paper on Le x . 7 Barrows et al 14 summarized the performance of the best MM methods for energies of D-glucose rotamers and they have found that HF/ 6-31G(d) method is clearly superior compared to any MM parametrization. Much effort has been made recently to parametrize molecular mechanics (MM) methods for saccharides in the gas phase using HF/6-31G(d) results.…”