2013
DOI: 10.1021/jp407115j
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Critical Role of Water in the Binding of Volatile Anesthetics to Proteins

Abstract: Numerous small molecules exhibit drug-like properties by low-affinity binding to proteins. Such binding is known to be influenced by water, the detailed picture of which, however, remains unclear. One particular example is the controversial role of water in the binding of general anesthetics to proteins as an essential step in general anesthesia. Here we demonstrate that a critical amount of hydration water is a prerequisite for anesthetic-protein binding. Using nuclear magnetic resonance, the concurrent adsor… Show more

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Cited by 11 publications
(22 citation statements)
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“…We propose here that dewetting of hydrophobic cavities upon anesthetic binding is the primary determinant of affinity for propofol and sevoflurane for intersubunit sites on GABA A receptors. This result is consistent with a previous observation, using NMR, that a critical level of hydration was required for halothane to bind to proteins (65). To our knowledge, this is the first time the number of displaced water molecules has been correlated with affinity to explain GA specificity and selectivity.…”
Section: Resultssupporting
confidence: 93%
“…We propose here that dewetting of hydrophobic cavities upon anesthetic binding is the primary determinant of affinity for propofol and sevoflurane for intersubunit sites on GABA A receptors. This result is consistent with a previous observation, using NMR, that a critical level of hydration was required for halothane to bind to proteins (65). To our knowledge, this is the first time the number of displaced water molecules has been correlated with affinity to explain GA specificity and selectivity.…”
Section: Resultssupporting
confidence: 93%
“…Our groups’ recent work elucidated the binding mechanism of halothane and other typical general anesthetics 40 . Halothane cannot directly bind to the protein in the absence of hydration.…”
Section: Discussionmentioning
confidence: 99%
“…Further hydration of the protein has smaller effects on the enthalpic and entropic changes but still results in significant decrease in Gibbs free energy upon alcohol binding. A significant difference is recognized between the role of water in alcohol binding and its role in the binding of other general anesthetics such as halothane 40 . The present work revealed the importance of water-protein interactions in alcohol binding.…”
Section: Introductionmentioning
confidence: 99%
“…Receptor mutation studies suggest that high-affinity propofol binding of GABA A receptors occurs at sites that are distinctly different from those that bind low-affinity volatile anesthetics, such as isoflurane [2] . Low-affinity binding sites are postulated to be amphipathic and water filled pockets within the receptor [3,4] . At least in the case of N-methyl-D-aspartate (NMDA) receptors, this low-affinity protein binding is subject to a cut-off effect associated with molar water solubility, but not molecular structure or size [5] .…”
Section: Introductionmentioning
confidence: 99%