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The Role of Bridging Water and Hydrogen Bonding as Key Determinants of Noncovalent Protein–Carbohydrate Recognition
Author(s) -
Ruvinsky Anatoly M.,
Aloni Ishita,
Cappel Daniel,
Higgs Chris,
Marshall Kyle,
Rotkiewicz Piotr,
Repasky Matt,
Feher Victoria A.,
Feyfant Eric,
Hessler Gerhard,
Matter Hans
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800437
Subject(s) - chemistry , hydrogen bond , amide , molecule , non covalent interactions , binding site , solvent , bridging (networking) , molecular recognition , stereochemistry , biochemistry , crystallography , organic chemistry , computer network , computer science
Abstract Mechanisms of protein–carbohydrate recognition attract a lot of interest due to their roles in various cellular processes and metabolism disorders. We have performed a large‐scale analysis of protein structures solved in complex with glucose, galactose and their substituted analogues. We found that, on average, sugar molecules establish five hydrogen bonds (HBs) in the binding site, including one to three HBs with bridging water molecules. The free energy contribution of bridging and direct HBs was estimated using the free energy perturbation (FEP+) methodology for mono‐ and disaccharides that bind to l ‐ABP, ttGBP, TrmB, hGalectin‐1 and hGalectin‐3. We show that removing hydroxy groups that are engaged in direct HBs with the charged groups of Asp, Arg and Glu residues, protein backbone amide or buried water dramatically decreases binding affinity. In contrast, all solvent‐exposed hydroxy groups and hydroxy groups engaged in HBs with the solvent‐exposed bridging water molecules contribute weakly to binding affinity and so can be replaced to optimize ligand potency. Finally, we rationalize an effect of binding site water replacement on the binding affinity to l ‐ABP.