Dataset Information

Defining the Specificity of Carbohydrate-Protein Interactions by Quantifying Functional Group Contributions.

ABSTRACT: Protein-carbohydrate interactions are significant in a wide range of biological processes, disruption of which has been implicated in many different diseases. The capability of glycan-binding proteins (GBPs) to specifically bind to the corresponding glycans allows GBPs to be utilized in glycan biomarker detection or conversely to serve as targets for therapeutic intervention. However, understanding the structural origins of GBP specificity has proven to be challenging due to their typically low binding affinities (mM) and their potential to display broad or complex specificities. Here we perform molecular dynamics (MD) simulations and post-MD energy analyses with the Poisson-Boltzmann and generalized Born solvent models (MM-PB/GBSA) of the Erythrina cristagalli lectin (ECL) with its known ligands, and with new cocrystal structures reported herein. While each MM-PB/GBSA parametrization resulted in different estimates of the desolvation free energy, general trends emerged that permit us to define GBP binding preferences in terms of ligand substructure specificity. Additionally, we have further decomposed the theoretical interaction energies into contributions made between chemically relevant functional groups. Based on these contributions, the functional groups in each ligand can be assembled into a pharmacophore comprised of groups that are either critical for binding, or enhance binding, or are noninteracting. It is revealed that the pharmacophore for ECL consists of the galactopyranose (Gal) ring atoms along with C6 and the O3 and O4 hydroxyl groups. This approach provides a convenient method for identifying and quantifying the glycan pharmacophore and provides a novel method for interpreting glycan specificity that is independent of residue-level glycan nomenclature. A pharmacophore approach to defining specificity is readily transferable to molecular design software and, therefore, may be particularly useful in designing therapeutics (glycomimetics) that target GBPs.

SUBMITTER: Sood A

PROVIDER: S-EPMC6442460 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Defining the Specificity of Carbohydrate-Protein Interactions by Quantifying Functional Group Contributions.

Sood Amika A Gerlits Oksana O OO Ji Ye Y Bovin Nicolai V NV Coates Leighton L Woods Robert J RJ

Journal of chemical information and modeling 20180822 9

Protein-carbohydrate interactions are significant in a wide range of biological processes, disruption of which has been implicated in many different diseases. The capability of glycan-binding proteins (GBPs) to specifically bind to the corresponding glycans allows GBPs to be utilized in glycan biomarker detection or conversely to serve as targets for therapeutic intervention. However, understanding the structural origins of GBP specificity has proven to be challenging due to their typically low ...[more]

PMID: 30086239

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Project description:Water-mediated interactions play a key role in carbohydrate-lectin binding, where the interactions involve a conserved water that is separated from the bulk solvent and present a bridge between the side chains of the protein and the carbohydrate ligand. To apply quantum mechanical methods to examine the role of conserved waters, we present an analysis in which the relevant carbohydrate atoms are modeled by methanol, and in which the protein is replaced by a limited number of amino acid side chains. Clusters containing a conserved water and a representative amino acid fragment were also examined to determine the influence of amino acid side chains on interaction energies. To quantify the differential binding energies of methanol versus water, quantum mechanical calculations were performed at the B3LYP/6-311++G(3df,3pd)//B3LYP/6-31+G(d) level in which either a methanol molecule was bound to the conserved water (liganded state) or in which a water molecule replaces the methanol (unliganded state). Not surprisingly, the binding of a water to clusters containing charged amino acid side chains was more favorable by 1.55 to 7.23 kcal/mol than that for the binding of a water to the corresponding pure water clusters. In contrast, the binding energy of water to clusters containing polar-uncharged amino acid side chains ranged from 4.35 kcal/mol less favorable to 4.72 kcal/mol more favorable than for binding to the analogous pure water clusters. The overall trend for the binding of methanol versus water, in any of the clusters, favored methanol by an average value of 1.05 kcal/mol. To extend these studies to a complex between a protein (Concanavalin A) and its carbohydrate ligand, a cluster was examined that contained the side chains of three key amino acids, namely asparagine, aspartate, and arginine, as well as a key water molecule, arranged as in the X-ray diffraction structure of Con A. Again, using methanol as a model for the endogenous carbohydrate ligand, energies of -5.94 kcal/mol and -5.70 kcal/mol were obtained for the binding of methanol and water, respectively, to the Con A-water cluster. The extent to which cooperativity enhanced the binding energies has been quantified in terms of nonadditive three-body contributions. In general, the binding of water or methanol to neutral dimers formed cooperative clusters; in contrast, the cooperativity in charged clusters depended on the overall geometry as well as the charge.

Project description:Interactions of proteins with functional groups are key to their biological functions, making it essential that they be accurately modeled. To investigate the impact of the inclusion of explicit treatment of electronic polarizability in force fields on protein-functional group interactions, the additive CHARMM and Drude polarizable force field are compared in the context of the Site-Identification by Ligand Competitive Saturation (SILCS) simulation methodology from which functional group interaction patterns with five proteins for which experimental binding affinities of multiple ligands are available, were obtained. The explicit treatment of polarizability produces significant differences in the functional group interactions in the ligand binding sites including overall enhanced binding of functional groups to the proteins. This is associated with variations of the dipole moments of solutes representative of functional groups in the binding sites relative to aqueous solution with higher dipole moments systematically occurring in the latter, though exceptions occur with positively charged methylammonium. Such variation indicates the complex, heterogeneous nature of the electronic environments of ligand binding sites and emphasizes the inherent limitation of fixed charged, additive force fields for modeling ligand-protein interactions. These effects yield more defined orientation of the functional groups in the binding pockets and a small, but systematic improvement in the ability of the SILCS method to predict the binding orientation and relative affinities of ligands to their target proteins. Overall, these results indicate that the physical model associated with the explicit treatment of polarizability along with the presence of lone pairs in a force field leads to changes in the nature of the interactions of functional groups with proteins versus that occurring with additive force fields, suggesting the utility of polarizable force fields in obtaining a more realistic understanding of protein-ligand interactions.

Dataset Information

Defining the Specificity of Carbohydrate-Protein Interactions by Quantifying Functional Group Contributions.

Publications

Defining the Specificity of Carbohydrate-Protein Interactions by Quantifying Functional Group Contributions.

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