Protein-carbohydrate interactions play crucial roles in biological processes from embryonic development to the immune response, but an understanding of the intermolecular forces that contribute to them is limited. We have found that aliphatic residues are underrepresented in carbohydrate binding sites  while aromatic residues are dramatically overrepresented. Our data indicate these aromatics can engage in CH-π interactions with the carbohydrates. Our goal is to understand the molecular basis for aromatic-carbohydrate interactions.<br/>Not all monosaccharides were effective CH-π donors. Amongst those tested, glycosides with multiple electron-poor CH bonds oriented in a similar direction were stronger CH-π donors, while those lacking such patches were poor donors.  A linear free energy study using substituted indoles (as tryptophan mimics) in water revealed that electronic effects contribute: compared to electron-poor aromatics,  electron-rich aromatics promoted more effective CH-π interactions. To assess the role of aromatic residues in the carbohydrate binding site of a protein, the lactose binding affinity of galectin-3 variants at the CH-π acceptor residue W181 was determined by isothermal titration calorimetry. In the lactose-binding protein galectin-3, we observed that replacement of W181 with an aliphatic methionine abrogated lactose binding.  Our findings highlight the importance of CH-π interactions for binding β-galactosides, a conclusion supported by binding data for galectin-3 variants.<br/>

Importance of aromatic residues in protein-carbohydrate interactions

256th National Meeting (2018)

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