Docking algorithms that aim to be applicable to as broad a range of ligands as possible are generally unable to incorporate ligand conformational energies. In the case of flexible ligands, which nevertheless have defined conformational preferences, such as oligosaccharides, the omission of internal energies leads to inaccurate predictions of the bound conformations of such ligands. We have developed an internal energy term to account for the rotational preferences of the glycosidic torsion angles in carbohydrates, by employing quantum mechanical calculations to obtain energy profiles from a series of representative models of hexopyranosyl disaccharides. The energy function mirrored the conformational distributions of glycosidic linkages determined from a survey of oligosaccharide-protein complexes present in the Protein Data Bank (PDB). This internal energy function was employed to evaluate the relative energies of oligosaccharides whose conformations were generated by flexible ligand docking using Autodock 3, 4.2, and Vina. Addition of the internal energy term to the docking scores, for six known antibody-carbohydrate systems, significantly improved the ranking of correct poses. This term was then integrated into Autodock Vina's scoring function in order to penalize unnatural carbohydrate conformations during docking, and evaluated using a larger and more challenging test set of 13 antibody-carbohydrate complexes. Models predicted by the new scoring function (Vina-Carb  ) matched or exceeded the accuracy of those output by Vina. This conformational energy term is independent of docking algorithm, and can therefore be used to score structures produced from any docking protocol. In addition, it may be employed to quantify the energetic cost of induced fit in a carbohydrate bound to a receptor, or to curate low-resolution crystallographic data. With minor modifications, the energy function may be incorporated into theoretical modeling methods, as well as into experimental NMR or X-ray structure refinement programs, to assist in producing reliable 3D structures for oligosaccharides.

Importance of ligand conformational energies in carbohydrate docking: Sorting the wheat from the chaff

246th National Meeting (2013)

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