GlycoTorch Vina: Docking Designed and Tested for Glycosaminoglycans

Abstract

Glycosaminoglycans (GAGs) are a family of anionic carbohydrates that play an essential role in the physiology and pathology of all eukaryotic life forms. Experimental determination of GAG–protein complexes is challenging due to their difficult isolation from biological sources, natural heterogeneity, and conformational flexibilityincluding possible ring puckering of sulfated iduronic acid from 1C4 to 2SO conformation. To overcome these challenges, we present GlycoTorch Vina (GTV), a molecular docking tool based on the carbohydrate docking program VinaCarb (VC). Our program is unique in that it contains parameters to model 2SO sugars while also supporting glycosidic linkages specific to GAGs. We discuss how crystallographic models of carbohydrates can be biased by the choice of refinement software and structural dictionaries. To overcome these variations, we carefully curated 12 of the best available GAG and GAG-like crystal structures (ranging from tetra- to octasaccharides or longer) obtained from the PDB-REDO server and refined using the same protocol. Both GTV and VC produced pose predictions with a mean root-mean-square deviation (RMSD) of 3.1 Å from the native crystal structurea statistically significant improvement when compared to AutoDock Vina (4.5 Å) and the commercial software Glide (5.9 Å). Examples of how real-space correlation coefficients can be used to better assess the accuracy of docking pose predictions are given. Comparisons between statistical distributions of empirical “salt bridge” interactions, relevant to GAGs, were compared to density functional theory (DFT) studies of model salt bridges, and water-mediated salt bridges; however, there was generally a poor agreement between these data. Water bridges appear to play an important, yet poorly understood, role in the structures of GAG–protein complexes. To aid in the rapid prototyping of future pose scoring functions, we include a module that allows users to include their own torsional and nonbonded parameters.

Structural Insights into Pixatimod (PG545) Inhibition of Heparanase, a Key Enzyme in Cancer and Viral Infections

“… [11a] Attempts to similarly dock PG545 using SeeSAR were unsuccessful because SeeSAR cannot dock ligands on the surface. PG545 was therefore docked using GlycoTorch Vina, [25] a ligand−protein docking program specifically developed for HS−protein interactions, which provided a ligand−protein complex. Several ligand−protein complexes of different conformations were obtained on docking from which two conformations were selected which blocked the catalytic residues (Glu225 and 343) essential for cleaving substrate (Figure 5 ).…”

Modeling Protein–Glycosaminoglycan Complexes: Does the Size Matter?

“…At the same time, it is important to mention that our approach is not limited to any special docking software. We expect that carbohydrate- and GAG-specific docking programs as Vina-Carb 56 or GlycoTorch Vina, 57 respectively, which also belong to the family of Autodock programs, would perform similarly or even outperform Autodock3 for obtaining the initial structures of protein/peptide complexes with short GAGs that are to be further elongated using the procedure proposed in this manuscript. In this procedure, we elongate a docked GAG using the CG model for the monosaccharide units and use it in conventional MD simulations.…”

Systemic Lectin-Glycan Interaction of Pathogenic Enteric Bacteria in the Gastrointestinal Tract

“…These protein-ligand or sugar chain-lectin ligand docking programs are used to understand the functions of the ligands by predicting their binding structure. These programs are also used to discover and optimize the binding site and candidate materials [62][63][64]. It is essential to predict the binding pose with high accuracy.…”