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

Area of Science:

• Biochemistry and structural biology
• Computational chemistry and molecular modeling
• Glycoscience and glycobiology

Background:

• Protein-carbohydrate interactions mediated by glycan-binding proteins (GBPs) are vital in biological processes.
• Disruptions in these interactions are linked to various diseases, highlighting the therapeutic potential of targeting GBPs.
• Understanding the structural basis of GBP specificity is challenging due to low binding affinities and complex recognition patterns.

Purpose of the Study:

• To elucidate the structural origins of Erythrina cristagalli lectin (ECL) specificity for its glycan ligands.
• To develop a novel computational approach for defining glycan pharmacophores and interpreting specificity.
• To identify key functional groups within glycans that are critical for binding to GBPs.

Main Methods:

• Molecular dynamics (MD) simulations were performed on ECL in complex with its known ligands.
• Post-MD energy analyses using MM-PB/GBSA methods were employed to estimate binding free energies.
• Interaction energies were decomposed into contributions from chemically relevant functional groups to define a pharmacophore.

Main Results:

• General trends in GBP binding preferences were identified based on ligand substructure specificity.
• A pharmacophore for ECL was defined, comprising galactopyranose ring atoms and specific hydroxyl groups (O3, O4) and C6.
• The approach provides a residue-level-independent method for quantifying glycan pharmacophores.

Conclusions:

• The developed pharmacophore approach offers a convenient method for identifying and quantifying glycan binding determinants.
• This novel interpretation of glycan specificity is transferable to molecular design software.
• The findings can guide the rational design of glycomimetics for therapeutic interventions targeting GBPs.