Paper Citing NAMD - Abstract
Willenbring, Dan; Xu, Yan; Tang, Pei
The role of structured water in mediating general anesthetic action on alpha 4 beta 2 nAChR
PHYSICAL CHEMISTRY CHEMICAL PHYSICS, 12:10263-10269, 2010
Water is an essential component for many biological processes. Pauling proposed that water might play a critical role in general anesthesia by forming water clathrates 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-channel nAChR 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 water clusters suggests that the formation of water clathrates is unlikely to be a primary cause for anesthesia. Despite the decrease in water population at most of the halothane binding 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 agonist binding 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 water clathrates around anesthetics.
