Relative energies of binding for antibody-carbohydrate-antigen complexes computed from free-energy simulations - PubMed (original) (raw)

Relative energies of binding for antibody-carbohydrate-antigen complexes computed from free-energy simulations

A Pathiaseril et al. J Am Chem Soc. 2000.

Abstract

Free-energy perturbation (FEP) simulations have been applied to a series of analogues of the natural trisaccharide epitope of Salmonella serotype B bound to a fragment of the monoclonal anti-Salmonella antibody Se155-4. This system was selected in order to assess the ability of free-energy perturbation (FEP) simulations to predict carbohydrate-protein interaction energies. The ultimate goal is to use FEP simulations to aid in the design of synthetic high affinity ligands for carbohydrate-binding proteins. The molecular dynamics (MD) simulations were performed in the explicit presence of water molecules, at room temperature. The AMBER force field, with the GLYCAM parameter set for oligosaccharides, was employed. In contrast to many modeling protocols, FEP simulations are capable of including the effects of entropy, arising from differential ligand flexibilities and solvation properties. The experimental binding affinities are all close in value, resulting in small relative free energies of binding. Many of the DeltaDeltaG values are on the order of 0-1 kcal mol(-1), making their accurate calculation particularly challenging. The simulations were shown to reasonably reproduce the known geometries of the ligands and the ligand-protein complexes. A model for the conformational behavior of the unbound antigen is proposed that is consistent with the reported NMR data. The best agreement with experiment was obtained when histidine 97H was treated as fully protonated, for which the relative binding energies were predicted to well within 1 kcal mol(-1). To our knowledge this is the first report of FEP simulations applied to an oligosaccharide-protein complex.

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Figures

Figure 1

Figure 1

Hydrogen bonds between the wild-type antigen (1) and the residues in the combining site of the Fab fragment of Se155-4.

Figure 2

Figure 2

MD trajectories for the wild-type ligand in water. (A) Glycosidic torsion angles for the Gal-α-(1→2)-Man linkage computed with the GLYCAM_93 parameters. (B) Glycosidic torsion angles for the Abe-α-(1→3)Man linkage computed with the GLYCAM_93 parameters. (C) As in (A), but computed with the GLYCAM_98R parameters. (D) As in (B), but computed with the GLYCAM_98R parameters.

Scheme 1

Scheme 1

Scheme 2

Scheme 2

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