Noble gas molecules partitioning

At dynamical equilibrium, noble gas molecules (Ne, Ar, Kr and Xe) within the bilayer account for 77.3%, 85.2%, 91.0% and 95.7% of the total, initially localized in the aqueous phase. According to the Meyer-Overton correlation, the greater the lipid/water partitioning coefficient is, the stronger its anesthetic potency is. Therefore, our simulation results are in good agreement with this rule. Although the partitioning percentage presents a little fluctuation because of different gas concentration, the results still obey the correlation after equilibrium.

The partitioning of the noble gases within the bilayer can be more quantitatively illustrated by the noble gas density distributions. Figure 1 shows the densities of the z direction of four kinds of noble gases. The peak of each curve is at the center of the bilayer for all systems, indicating that noble gas molecules are preferentially aggregated at the center of the membrane, since there is an interspace between the upper and lower leaflets. This localization of gas molecules is almost the same as previous simulations performed by Stimson et al. and Yamamoto et al.28,29,41. However, the probability of xenon localizing near the lipid head groups is about 10% higher than those of the other three gases (Ne, Ar and Kr), which is of great importance to explain xenon’s strong narcotic efficacy. Yamamoto proposed that the narcotic function of xenon will be decreased when xenon molecules move to the hydrophobic core of the lipid bilayer and are jammed there under high pressures. Other anesthetics, such as halothane, diethyl ether, enflurane and ethanol, prefer two different positions, namely the center of the membrane and the hydrocarbon region, close to the polar headgroups5,42,43. Therefore, we suggest that the narcotic potency of xenon is much stronger because more xenon molecules than other noble gases are distributed between the lipid tails and headgroups. This speculation can be further confirmed at higher noble gas concentration (3 noble gas atoms per lipid). As shown in Fig. 2, about 90% neon atoms are congested in the middle of the membrane and stretch the bilayer at the normal direction, while about 40% xenon atoms diffuse near the hydrocarbon region and expand the membrane at the lateral direction.

Figure 1 Density of the z direction of four kinds of noble gases (Ne, black, Ar, red, Kr, green and Xe blue), where the z axis is normal to the lipid bilayer. The center of the lipid bilayer is fixed at z = 0 nm. Full size image

Figure 2 Results of 3 noble gas molecules per lipid system. (a) Density distribution. (b,c) are final snapshots at t = 200 ns. Carbon (cyan), oxygen (red), nitrogen (blue) and phosphorous (tan) in head groups are shown using spheres while the lipid tails are shown as dynamic-bonds. Xenon and neon molecules are depicted as green and yellow balls. Water molecules are omitted for clarity. The images are created by VMD software. Full size image

Effects of noble gases on membrane structure

Figure 3 shows area per lipid S, thickness h and volume V in the five independent systems. The area per lipid is defined as the area of the xy-plane of the simulation box divided by the number of lipids per leaflet. The thickness of lipid bilayer h is defined as the distance between the average z-position of the phosphorus atom in the two layers. And the volume per lipid is defined as V = Sh/2. In general, the three parameters containing noble gases are bigger than those of pure hydrated membrane. Furthermore, it is interesting to find that the values of S and V rise gradually in the order of Ne, Ar, Kr and Xe, which is in agreement with the sequence of their narcotic potencies from weak to strong. The area per lipid and volume with xenon increase at the most by 12.2% and 9.54%, respectively. However, the thickness h does not hold this trend, especially xenon, as shown in Fig. 3b. For example, the thickness with argon increases 0.87%, while h with xenon decreases 0.33%, compared with pure membrane. The thickness h is mainly determined by two factors: the distributions of gas molecules and lipid tail ordering. As mentioned above, xenon within the membrane leads to its lateral expansion more than normal stretch.

Figure 3 Effects of noble gas molecules on bilayer structural properties. (a) Area per lipid, (b) thickness and (c) volume per lipid. Error bars mean the root mean square deviations. Full size image

The localization of noble gases in the hydrophobic core of the bilayer has substantial effects on the ordering of the lipid acyl chains. Figure 4 shows the two lipid tail (sn-1 and sn-2) deuterium order parameters of five systems. The deuterium order is defined by

Figure 4 Lipid tail order parameters of (a) sn-1 chain and (b) sn-2 chain. (c) Atomic structure of POPE (cyan, red, blue and tan balls represent carbon, oxygen, nitrogen and phosphorus atoms, respectively). Full size image