Understanding the Molecular Mechanism of Anesthesia: Effect of General Anesthetics and Structurally Similar Non-Anesthetics on the Properties of Lipid Membranes

General anesthesia can be caused by various, chemicallyvery differentmolecules, while several other molecules, many of which are structurallyrather similar to them, do not exhibit anesthetic effects at all.To understand the origin of this difference and shed some light onthe molecular mechanism of general anesthesia, we report here moleculardynamics simulations of the neat dipalmitoylphosphatidylcholine (DPPC)membrane as well as DPPC membranes containing the anesthetics diethylether and chloroform and the structurally similar non-anesthetics n-pentane and carbon tetrachloride, respectively. To alsoaccount for the pressure reversal of anesthesia, these simulationsare performed both at 1 bar and at 600 bar. Our results indicate thatall solutes considered prefer to stay both in the middle of the membraneand close to the boundary of the hydrocarbon domain, at the vicinityof the crowded region of the polar headgroups. However, this latterpreference is considerably stronger for the (weakly polar) anestheticsthan for the (apolar) non-anesthetics. Anesthetics staying in thisouter preferred position increase the lateral separation between thelipid molecules, giving rise to a decrease of the lateral density.The lower lateral density leads to an increased mobility of the DPPCmolecules, a decreased order of their tails, an increase of the freevolume around this outer preferred position, and a decrease of thelateral pressure at the hydrocarbon side of the apolar/polar interface,a change that might well be in a causal relation with the occurrenceof the anesthetic effect. All these changes are clearly reverted bythe increase of pressure. Furthermore, non-anesthetics occur in thisouter preferred position in a considerably smaller concentration andhence either induce such changes in a much weaker form or do not inducethem at all.