The role of structured water in mediating general anesthetic action on alpha 4 beta 2 nAChR

Water is an essential component for many biological processes. Pauling proposed that water might play a critical role in general anesthesia by forming waterclathrates around anesthetic molecules. To examine potential involvement of water in general anesthesia, we analyzed water within alpha 4 beta 2...

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Bibliographic Details
Published in:Physical chemistry chemical physics : PCCP 2010-08, Vol.12 (35), p.10263-10269
Main Authors: Willenbring, Dan, Xu, Yan, Tang, Pei
Format: Article
Language:English
Subjects:
Anesthesia
Anesthetics
Binding sites
Channels
Dynamical systems
Dynamics
Forming
Proteins
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Summary:Water is an essential component for many biological processes. Pauling proposed that water might play a critical role in general anesthesia by forming waterclathrates around anesthetic molecules. To examine potential involvement of water in general anesthesia, we analyzed water within alpha 4 beta 2 nAChR, a putative protein target hypersensitive to volatile anesthetics. Experimental structure-derived closed- and open-channelnAChR systems in a fully hydrated lipid bilayer were examined using all-atom molecular dynamics simulations. At the majority of binding sites in alpha 4 beta 2 nAChR, halothane replaced the slow-exchanging water molecules and caused a regional water population decrease. Only two binding sites had an increased quantity of water in the presence of halothane, where water arrangements resemble clathrate-like structures. The small number of such clathrate-like waterclusters suggests that the formation of waterclathrates is unlikely to be a primary cause for anesthesia. Despite the decrease in water population at most of the halothanebinding sites, the number of sites that can be occupied transiently by water is actually increased in the presence of halothane. Many of these water sites were located between two subunits or in regions containing agonistbinding sites or critical structural elements for transducing agonist binding to channel gating. Changes in water sites in the presence of halothane affected water-mediated protein-protein interactions and the protein dynamics, which can have direct impact on protein function. Collectively, water contributes to the action of anesthetics in proteins by mediating interactions between protein subunits and altering protein dynamics, instead of forming waterclathrates around anesthetics.
ISSN:1463-9076
1463-9084
DOI:10.1039/c003573d