2019
DOI: 10.1021/jacs.9b06275
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Water Networks Can Determine the Affinity of Ligand Binding to Proteins

Abstract: Solvent organization is a key but underexploited contributor to the thermodynamics of protein−ligand recognition, with implications for ligand discovery, drug resistance, and protein engineering. Here, we explore the contribution of solvent to ligand binding in the Haemophilus influenzae virulence protein SiaP. By introducing a single mutation without direct ligand contacts, we observed a >1000-fold change in sialic acid binding affinity. Crystallographic and calorimetric data of wild-type and mutant SiaP show… Show more

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Cited by 126 publications
(131 citation statements)
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“…The observed gain in entropy for AMPPNP/ADP:Hsp90NMD systems could be attributed to the conformational changes of Hsp90NMD and/or the perturbation of hydration network of the chaperone protein, which are induced by the binding of SOMCL-16-171 or SOMCL-16-175. Since the water/hydration network could be considered as a component of protein structure, the perturbation of hydration network caused by ligand binding is therefore intimately coupled to protein conformational changes (Biela et al, 2013;Chandler, 2005;Darby et al, 2019). Therefore, the ITC data confirm that the binding of the active compounds to Hsp90a's middle domain does allosterically modulate the conformations of Hsp90a's N-terminal domain in solution.…”
Section: Somcl-16-171 and Somcl-16-175 Are Allosteric Modulators Of Hmentioning
confidence: 73%
“…The observed gain in entropy for AMPPNP/ADP:Hsp90NMD systems could be attributed to the conformational changes of Hsp90NMD and/or the perturbation of hydration network of the chaperone protein, which are induced by the binding of SOMCL-16-171 or SOMCL-16-175. Since the water/hydration network could be considered as a component of protein structure, the perturbation of hydration network caused by ligand binding is therefore intimately coupled to protein conformational changes (Biela et al, 2013;Chandler, 2005;Darby et al, 2019). Therefore, the ITC data confirm that the binding of the active compounds to Hsp90a's middle domain does allosterically modulate the conformations of Hsp90a's N-terminal domain in solution.…”
Section: Somcl-16-171 and Somcl-16-175 Are Allosteric Modulators Of Hmentioning
confidence: 73%
“…Although it is difficult to assess the exact cause of these relatively small distance variations between X-ray and cryoEM structures, it is reasonable to conclude that many of the waters in the X-ray structure are also resolved and near the same positions in cryoEM maps. Water networks have been shown to be important in ligand binding affinities and to vary due to structural differences even in X-ray structures 28 . Further studies with more cryoEM maps at similar resolutions may further elucidate and characterize such variations.…”
Section: Resultsmentioning
confidence: 99%
“…Their conformational transition upon ligand binding involves a twist of rigid protein domains around a fixed axis (''hinge-bending'' motions). [37][38][39][40] These transitions do not alter the flexibility of individual protein domains to an extent as observed in FimH and can be considered entropically neutral. Thus, modulation of binding site permittivity could represent a general mechanism for carbohydrate binding proteins to enable enthalpy-driven recognition of polar ligands in aqueous solution.…”
Section: Resultsmentioning
confidence: 89%