Although general anesthesia is used in the surgical practice for more than one and a half centuries, its molecular mechanism is still largely unknown. Well-established scientific results only indicate that the site of its action is the cell membrane, and the anesthetic effect is reverted at high pressure. Also, there is a growing consensus that whatever this mechanism is, it only affects certain properties of the cell membrane directly, while it affects only indirectly, through these membrane-related changes, the conformation of the relevant membrane-bound proteins.
Based on computer simulation results, here we propose a potential molecular mechanism which, together with the Cantor hypothesis (i.e., that anesthetics-induced non-uniform changes in the lateral pressure profile can result in a conformational switch of the related, most likely channel-forming proteins) can provide a causal explanation of general anesthesia. The key point is that the main positional preference of the slightly polar or strongly polarizable general anesthetics – unlike that of chemically or, at least structurally similar non-anesthetics – is to stay at the apolar side of the apolar/polar interface, close to the dense region of the polar headgroups. Anesthetics located in this region push the nearby lipid tails farther away from each other, leading to a lateral swelling of the membrane which, in turn, increases lipid mobility and the free volume fraction, and decreases lipid tail ordering. More importantly, pushing the lipid molecules farther away from each other leads to a weakening of their lateral interaction, in particular, close to the position of the anesthetics and also in the dense region of the strongly interacting polar headgroups. As a consequence, lateral pressure decreases in the presence of anesthetics (while, evidently, it increases with increasing pressure) at the polar side of the apolar/polar interface, at the region of the ester groups, providing thus the non-uniform change of the lateral pressure profile required by the Cantor hypothesis.