Vina-Carb: Improving Glycosidic Angles during Carbohydrate Docking

Abstract

Molecular docking programs are primarily designed to align rigid, drug-like fragments into the binding sites of macromolecules and frequently display poor performance when applied to flexible carbohydrate molecules. A critical source of flexibility within an oligosaccharide is the glycosidic linkages. Recently, Carbohydrate Intrinsic (CHI) energy functions were reported that attempt to quantify the glycosidic torsion angle preferences. In the present work, the CHI-energy functions have been incorporated into the AutoDock Vina (ADV) scoring function, subsequently termed Vina-Carb (VC). Two user-adjustable parameters have been introduced, namely, a CHI- energy weight term (chi_coeff) that affects the magnitude of the CHI-energy penalty and a CHI-cutoff term (chi_cutoff) that negates CHI-energy penalties below a specified value. A data set consisting of 101 protein–carbohydrate complexes and 29 apoprotein structures was used in the development and testing of VC, including antibodies, lectins, and carbohydrate binding modules. Accounting for the intramolecular energies of the glycosidic linkages in the oligosaccharides during docking led VC to produce acceptable structures within the top five ranked poses in 74% of the systems tested, compared to a success rate of 55% for ADV. An enzyme system was employed in order to illustrate the potential application of VC to proteins that may distort glycosidic linkages of carbohydrate ligands upon binding. VC represents a significant step toward accurately predicting the structures of protein–carbohydrate complexes. Furthermore, the described approach is conceptually applicable to any class of ligands that populate well-defined conformational states.

Residue‐centric modeling and design of saccharide and glycoconjugate structures

“…We implemented the CHI Energy Function developed in the laboratory of Robert Woods. This function was determined from QM calculations involving various isomers of O ‐linked tetrahydropyran oligomers and confirmed by statistical data . This new scoring method is analogous to the Ramachandran scoring method used within Rosetta for peptide bonds.…”

“…When the LinkageConformerMover does not find a residue pair within the map of LinkageConformerData, a conformer is selected from the minima of the appropriate CarboHydrate‐Intrinsic (CHI) Energy Functions, which we describe below.…”

“…For scoring glycosidic φ torsion angles, the function depends on the stereochemistry of the anomeric carbon, and for scoring the ψ angle, it depends on whether the connecting oxygen atom is in the axial or equatorial position. (Omega angles were added to the CHI scoring function during the writing of this manuscript and have not yet been implemented in Rosetta.) The anomeric stereochemistry is read from CarbohydrateInfo.…”

Applying Pose Clustering and MD Simulations To Eliminate False Positives in Molecular Docking

“…The root-mean-squared deviation (RMSD) between the positions of the ring atoms of the docked ligands and the corresponding positions in the crystallographic co-complexes were computed for all of the systems. An RMSD of 2 Å or less was considered an acceptable pose 51 and an indication of a successful docking result. In 8 of the 10 systems, an acceptable pose was found consistently in each independent docking experiment, and it was also the top-ranked pose in six of the systems (Table 2).…”

“…Docking was performed using Vina-Carb (VC), a recently modified version of AutoDock Vina 40 that incorporates the conformational preferences of oligosaccharides. 39 Vina-Carb was selected because it biases the docking in favor of probable oligosaccharide shapes. The Dock/Cluster/MD approach was applied to 10 antibody carboydrate co-complexes and to three unliganded (apo) anticarbohydrate antibodies.…”