Ab initio conformational space study of model compounds of O-glycosidesof serine diamide

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Relative stabilities of rotamers of the N-acetyl-O-(2-acetamido-2-deoxy-α-D-galactopyranosyl)-L-seryl-N'-methyl amide (1) and eleven analogous molecules containing β-galactose, α- and β-mannose, α- and β-glucose, and L-threonine were calculated to learn whether they could explain the natural preference for 1 in linkages between the carbohydrate and protein in glycoproteins. The lowest energy rotamers of four O-glycoside models of serine diamide were identified with a Monte Carlo search coupled with molecular mechanics (MM2*). These rotamers were further optimized with an ab initio level of theory (HF/6-31G(d)). Subsequently, B3LYP/6-31+G(d) single point energies were calculated for the most stable HF structures. The most favorable interactions are present in 1 and its glucose analogue. The monosaccharide for the carbohydrate antenna is anchored to the serine residue with an 8/AcNH ··· O=C-NHMe hydrogen bond in the most stable rotamers. The mannose analogue and the β-anomers are considerably less stable according to the MM2* and especially to the ab inito energy values. The three analogues have HF/6-31G(d) energies which are 4-6 kcal mol-1 higher; the single point B3LYP/6-31+G(d)//HF/6-31G(d) calculations yield preferences of 3-5 kcal mol-1 for 1. The most stable L-threonine analogues show a behaviour very similarly to the corresponding serine analogues. The ZPE and thermal correction components of the calculated ΔH298 and ΔG298 values are relatively small (<0.4 kcal mol-1). However, the TΔS298 term can be as large as 2.6 kcal mol-1. The entropy terms stabilize the α-anomers relative to β-anomers, and ManNAc relative to GalNAc. The largest stabilization effect is observed for one of the rotamers of the α-anomer of ManNAc.

Original languageEnglish
Pages (from-to)4718-4733
Number of pages16
JournalChemistry - A European Journal
Issue number20
Publication statusPublished - Oct 18 2002


  • Computer chemistry
  • Density functional calculations
  • Gibbs free energies
  • Glycopeptides
  • Heats of formation

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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