What anaesthetics do to a cell membrane
Volatile anaesthetics are chemically very different, yet they act alike. Our simulations show what they do to the membrane around the proteins they target.
Few drugs behave like volatile anaesthetics. They are chemically very different from one another, the dose that works is close to the dose that harms, they are breathed in rather than swallowed or injected, and their effect wears off completely. How they act is still an open question.
A clue from oil
More than a century ago, people noticed that the more an anaesthetic likes oily, water-repelling environments, the more potent it is. Today there is a lot of evidence that anaesthetics act on proteins that sit inside the cell membrane. Those proteins are surrounded by lipids, and the two are tightly linked, so it makes sense to ask what anaesthetics do to the lipids themselves.
What we simulated
We built a model lipid bilayer, the double layer of fat molecules that forms a cell membrane, and ran microsecond-long molecular dynamics simulations with four small molecules at different concentrations:
- ethylene
- desflurane
- methoxyflurane
- a compound called F6 (1,2-dichlorohexafluorocyclobutane), which is chemically similar but does not cause immobility the way anaesthetics do
What changed
As the molecules moved into the membrane, the lipids became less ordered and the bilayer got thinner. Lipids moved sideways more easily, and each one took up more area. Most strikingly, the membrane became markedly less stiff, and how much softer it got tracked how water-repelling each compound was.
A softer, thinner, more fluid membrane changes the environment of every protein embedded in it. That is one way molecules this small and this different could still have a common effect.
Read the paper: Zizzi, Cavaglià, Tuszynski, Deriu, iScience 25(3), 103946 (2022). doi:10.1016/j.isci.2022.103946