Large-scale molecular dynamics simulations of general anesthetic effects on the ion channel in the fully hydrated membrane: The implication of molecular mechanisms of general anesthesia

Abstract

Interactions of volatile anesthetics with the central nervous system are characterized by low yet specific binding affinities. Although neurotransmitter-gated ion channels are considered the primary anesthetic targets, the mechanism of action at the molecular level remains elusive. We consider here the theoretical implications of channel dynamics on anesthetic action in a simplified membranechannel system. Large-scale 2.2-ns all-atom molecular dynamics simulations were performed to study the effects of halothane, a clinical anesthetic, on a gramicidin A (gA) channel in a fully hydrated dimyristoyl phosphatidylcholine membrane. In agreement with experimental results, anesthetics preferentially target the anchoring residues at the channel-lipid-water interface. Although the anesthetic effect on channel structure is minimal, the presence of halothane profoundly affects channel dynamics. For 2.2-ns simulation, the rms fluctuation of gA backbone in the lipid core increases from Ϸ1 Å in the absence of anesthetics to Ϸ1.5 Å in the presence of halothane. Autocorrelation analysis reveals that halothane (i) has no effect on the subpicosecond librational motion, (ii) prolongs the backbone autocorrelation time in the 10-to 100-ps time scale, and (iii) significantly decreases the asymptotic values of generalized order parameter and correlation time of nanosecond motions for the inner but not the outer residues. The simulation results discount the viewpoint of a structure-function paradigm that overrates the importance of structural fitting between general anesthetics and yet-unidentified hydrophobic protein pockets. Instead, the results underscore the global, as opposed to local, effects of anesthetics on protein dynamics as the underlying mechanisms for the action of general anesthetics and possibly of other low-affinity drugs.

Fluorine-19 NMR and computational quantification of isoflurane binding to the voltage-gated sodium channel NaChBac

“…general anesthetics | drug-protein interaction | voltage-gated sodium channel | nuclear magnetic resonance | molecular dynamics simulation G eneral anesthetics disrupt sensory communications by modulating proteins in the central nervous system (1)(2)(3)(4). For many years, the physiological relevance of a protein class to general anesthesia has been judged based on the protein's sensitivity to anesthetics, particularly the steepness of the in vitro concentration dependence, in comparison with that of the in vivo doseresponses.…”

Dipole Potential and Head-Group Spacing Are Determinants for the Membrane Partitioning of Pregnanolone

“…Cantor (1997) suggested a mechanism linking the membrane lateral-pressure profile to the action of membrane proteins. The importance of nonspecific interactions mediated by the amino acid residues in the lipid-water-protein interface was highlighted in a recent molecular-dynamics simulation of the effects of an anesthetic on gramicidin channels in membranes (Tang and Xu, 2002).The nongenomic effects of steroids, such as anesthesia, require higher steroid concentrations to manifest themselves than those mediated by the nuclear steroid receptors (Duval et al, 1983). Although these nongenomic effects are welldocumented, their mechanisms are still in dispute, and a number of molecular-level events could be involved.…”

“…Cantor (1997) suggested a mechanism linking the membrane lateral-pressure profile to the action of membrane proteins. The importance of nonspecific interactions mediated by the amino acid residues in the lipid-water-protein interface was highlighted in a recent molecular-dynamics simulation of the effects of an anesthetic on gramicidin channels in membranes (Tang and Xu, 2002).…”

Halothane Directly Modifies Na+ and K+ Channel Activities in Cultured Human Alveolar Epithelial Cells

“…Halogenated gases modify membrane fluidity and/or membrane proteins (Tang and Xu, 2002;Hauet et al, 2003). ENaCs respond to changes in lipid membrane properties induced by temperature (Chraibi and Horisberger, 2002) or by lipid-perturbing agents (Awayda et al, 2004) by modifying the degree of their selfinhibition.…”

“…Halothane is known to influence membrane lipid bilayer fluidity through reorientation of the lipid tails (Hauet et al, 2003) and has been recently shown to increase the segmental order of the lipids close to the membrane surface in membrane simulation models (Pickholz et al, 2005). Halothane, which distributes at the liquid-aqueous interface of cell membranes, can partition into amphiphilic membrane domains, thereby potentially changing the behavior of transport proteins (Tang and Xu, 2002). Because ENaC activity decreases with decreasing lipid ordering (Awayda et al, 2004) and is stimulated by cooling, which increases lipid order (Chraibi and Horisberger, 2002), halogenated gases may, at least partly, change ENaC protein conformation through an increase in segmental order leading to an increase ENaC activity.…”