Stacking Interactions between Carbohydrate and Protein Quantified by Combination of Theoretical and Experimental Methods

Abstract

Carbohydrate – receptor interactions are an integral part of biological events. They play an important role in many cellular processes, such as cell-cell adhesion, cell differentiation and in-cell signaling. Carbohydrates can interact with a receptor by using several types of intermolecular interactions. One of the most important is the interaction of a carbohydrate's apolar part with aromatic amino acid residues, known as dispersion interaction or CH/π interaction. In the study presented here, we attempted for the first time to quantify how the CH/π interaction contributes to a more general carbohydrate - protein interaction. We used a combined experimental approach, creating single and double point mutants with high level computational methods, and applied both to Ralstonia solanacearum (RSL) lectin complexes with α-l-Me-fucoside. Experimentally measured binding affinities were compared with computed carbohydrate-aromatic amino acid residue interaction energies. Experimental binding affinities for the RSL wild type, phenylalanine and alanine mutants were −8.5, −7.1 and −4.1 kcal.mol−1, respectively. These affinities agree with the computed dispersion interaction energy between carbohydrate and aromatic amino acid residues for RSL wild type and phenylalanine, with values −8.8, −7.9 kcal.mol−1, excluding the alanine mutant where the interaction energy was −0.9 kcal.mol−1. Molecular dynamics simulations show that discrepancy can be caused by creation of a new hydrogen bond between the α-l-Me-fucoside and RSL. Observed results suggest that in this and similar cases the carbohydrate-receptor interaction can be driven mainly by a dispersion interaction.

Landscape ofπ–πand sugar–πcontacts in DNA–protein interactions

“…Most importantly, these interactions display a range of binding energies in nature, including those equivalent to the strength of nucleobaseamino acid π-π contacts (up to −70 kJ mol −1 ) (Wilson et al, 2014). This was the first evidence that DNAprotein sugar-π contacts can be stronger than reported for carbohydrate-π interactions (Spiwok et al, 2004(Spiwok et al, , 2006Sujatha, Sasidhar, & Balaji, 2004;Wimmerová et al, 2012).…”

Deciphering the Glycan Preference of Bacterial Lectins by Glycan Array and Molecular Docking with Validation by Microcalorimetry and Crystallography

“…The particular localization of one tryptophan residue excludes the low energy conformation of Lewis oligosaccharide from the binding site. The strong stacking interaction that fucose establishes with this tryptophan residue in the binding site of RSL, a lectin closely related to BambL, was recently quantified [57]. Solving the crystal structure of BambL/Lewis x complex demonstrated that indeed, the fucose is bound with stacking to Trp, but that either the adjacent glycosidic linkages or the GlcNAc ring are distorted in order to adjust.…”

Quantum mechanics approaches to drug research in the era of structural chemogenomics

“…38 For example, atomic partial charges in the ligand or the binding site may vary from those assigned by the utilized force field due to polarization or charge transfer – the effect that is frequently observed with enzymes and metalloproteins. 39 Halogen bonds, CH-π, 40,41 π-π and cation-π interactions are usually not accounted for at sufficient accuracy. In some configurations, London dispersion forces may not be properly approximated by the widely used potentials.…”