Exploring volatile general anesthetic binding to a closed membrane-bound bacterial voltage-gated sodium channel via computation.
Despite the clinical ubiquity of anesthesia, the molecular basis of anesthetic action is poorly understood. Amongst the many molecular targets proposed to contribute to anesthetic effects, the voltage gated sodium channels (VGSCs) should also be considered relevant, as they have been shown to be sen...
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doaj-be59cb77fea54771a0fbbb62e90b1a2d2020-11-24T21:58:58ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582013-01-0196e100309010.1371/journal.pcbi.1003090Exploring volatile general anesthetic binding to a closed membrane-bound bacterial voltage-gated sodium channel via computation.S G RajuAnnika F BarberDavid N LeBardMichael L KleinVincenzo CarnevaleDespite the clinical ubiquity of anesthesia, the molecular basis of anesthetic action is poorly understood. Amongst the many molecular targets proposed to contribute to anesthetic effects, the voltage gated sodium channels (VGSCs) should also be considered relevant, as they have been shown to be sensitive to all general anesthetics tested thus far. However, binding sites for VGSCs have not been identified. Moreover, the mechanism of inhibition is still largely unknown. The recently reported atomic structures of several members of the bacterial VGSC family offer the opportunity to shed light on the mechanism of action of anesthetics on these important ion channels. To this end, we have performed a molecular dynamics "flooding" simulation on a membrane-bound structural model of the archetypal bacterial VGSC, NaChBac in a closed pore conformation. This computation allowed us to identify binding sites and access pathways for the commonly used volatile general anesthetic, isoflurane. Three sites have been characterized with binding affinities in a physiologically relevant range. Interestingly, one of the most favorable sites is in the pore of the channel, suggesting that the binding sites of local and general anesthetics may overlap. Surprisingly, even though the activation gate of the channel is closed, and therefore the pore and the aqueous compartment at the intracellular side are disconnected, we observe binding of isoflurane in the central cavity. Several sampled association and dissociation events in the central cavity provide consistent support to the hypothesis that the "fenestrations" present in the membrane-embedded region of the channel act as the long-hypothesized hydrophobic drug access pathway.http://europepmc.org/articles/PMC3681623?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
S G Raju Annika F Barber David N LeBard Michael L Klein Vincenzo Carnevale |
spellingShingle |
S G Raju Annika F Barber David N LeBard Michael L Klein Vincenzo Carnevale Exploring volatile general anesthetic binding to a closed membrane-bound bacterial voltage-gated sodium channel via computation. PLoS Computational Biology |
author_facet |
S G Raju Annika F Barber David N LeBard Michael L Klein Vincenzo Carnevale |
author_sort |
S G Raju |
title |
Exploring volatile general anesthetic binding to a closed membrane-bound bacterial voltage-gated sodium channel via computation. |
title_short |
Exploring volatile general anesthetic binding to a closed membrane-bound bacterial voltage-gated sodium channel via computation. |
title_full |
Exploring volatile general anesthetic binding to a closed membrane-bound bacterial voltage-gated sodium channel via computation. |
title_fullStr |
Exploring volatile general anesthetic binding to a closed membrane-bound bacterial voltage-gated sodium channel via computation. |
title_full_unstemmed |
Exploring volatile general anesthetic binding to a closed membrane-bound bacterial voltage-gated sodium channel via computation. |
title_sort |
exploring volatile general anesthetic binding to a closed membrane-bound bacterial voltage-gated sodium channel via computation. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Computational Biology |
issn |
1553-734X 1553-7358 |
publishDate |
2013-01-01 |
description |
Despite the clinical ubiquity of anesthesia, the molecular basis of anesthetic action is poorly understood. Amongst the many molecular targets proposed to contribute to anesthetic effects, the voltage gated sodium channels (VGSCs) should also be considered relevant, as they have been shown to be sensitive to all general anesthetics tested thus far. However, binding sites for VGSCs have not been identified. Moreover, the mechanism of inhibition is still largely unknown. The recently reported atomic structures of several members of the bacterial VGSC family offer the opportunity to shed light on the mechanism of action of anesthetics on these important ion channels. To this end, we have performed a molecular dynamics "flooding" simulation on a membrane-bound structural model of the archetypal bacterial VGSC, NaChBac in a closed pore conformation. This computation allowed us to identify binding sites and access pathways for the commonly used volatile general anesthetic, isoflurane. Three sites have been characterized with binding affinities in a physiologically relevant range. Interestingly, one of the most favorable sites is in the pore of the channel, suggesting that the binding sites of local and general anesthetics may overlap. Surprisingly, even though the activation gate of the channel is closed, and therefore the pore and the aqueous compartment at the intracellular side are disconnected, we observe binding of isoflurane in the central cavity. Several sampled association and dissociation events in the central cavity provide consistent support to the hypothesis that the "fenestrations" present in the membrane-embedded region of the channel act as the long-hypothesized hydrophobic drug access pathway. |
url |
http://europepmc.org/articles/PMC3681623?pdf=render |
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