Simple diffusion of lipid-soluble molecules through phospholipid bilayer -- does anything get "stuck" in transit?

Question

It's a pretty elementary concept, and when I first learned of it I don't think I had the foundations to even think of such a question, but I found myself the other day thinking about the amphipathic nature of the phospholipids in the plasma membrane and why it might be that lipid-soluble molecules don't stay in between the layers (of the bilayer). I know that simple diffusion is a response to a concentration gradient, but consider a case where equilibrium is being restored and lipid-soluble molecules are diffusing from whatever extracellular matrix through the membrane and into the cytosol. Towards the end of this process, when equilibrium is nearly restored and the last few molecules are making their way into the cell, the rate of diffusion for these last couple molecules will be slower than those that diffused when the concentration difference was greater. Since the polar heads on the outside and inside of the bilayer are hydrophilic but the inner part, where the fatty acid tails are, is hydrophobic, what drives a molecule to leave the cozy, accepting, lipophilic environment of the middle (of the bilayer) to cross through the cytosolic-side rejecting polar heads and enter the cytosol?I understand that initially these molecules were moving into the cell in response to a difference in intracellular vs extracellular concentration, but I'm asking whether we would ever see a case where the gradient is nearly zero and a molecule in transit simply decides to reside in between the layers instead of crossing all the way into the cell; as if moving through the cytosolic polar head side is not worth the effort to reduce a nearly-zero gradient to zero.Please ask me if I can clarify my question in any way -- I'm finding it difficult to phrase. I asked my professor (who has her doctorate in toxicology & pharmacology) and she understood what I was asking but didn't have an answer.

Answer 1

This is quite an interesting question without a particularly satisfying answer.

In theory your prediction is possible. If the intracellular and extracellular concentration of a lipid are identical, I suppose a diffusing compound could in theory get stuck in that lipid tail. Note that for that to happen, we have to make the following assumptions:

1. The diffusion lipid molecule is small.

The lipid tail is usually 10-20 carbons in length. So large lipid molecules wouldn't get trapped and be able to go through both layers of the phospholipid during the diffusion in one go.

1. The diffusion rate is very high

Consider that as the equilibrium is being formed, the concentration gradient is probably approaching 0. In such cases, the rate of diffusion decreases as well. Somehow, the rate of diffusion needs to be prohibitively high even in such conditions for the possibility of something to get trapped. Because when the cell is near equilibrium, the force of diffusion cannot surpass the force of the electric charge of phosphate on the outside. The only way something could get trapped is if the cell reaches equilibrium very rapidly and something on its way inward gets stuck.

I think ultimately, in theory, it could happen in extremely rare cases. But consider that no true physiological process is in complete equilibrium. That trapped lipid could leave as soon as the gradient shifts again.

Answer 2

My educated best guess is no, molecules would not get stuck in the membrane. If the concentration gradient is passive, there will be an equilibrium established where some molecules are flowing between the inner and out environments. However, if the concentration gradient is active, the protein will prevent the molecule from getting stuck and successfully transferring it to it respective environment.

Answer 3

There may be some research on the subject out there but I can only offer a theory. While we like to describe the phospholipid bilayer as a static entity, the reality of it is that the membrane is highly fluid. Any individual phospholipid is most likely flipping from one side of the membrane to the other, leaving the membrane as a vesicle or rejoining the ER/lysosome during endocytosis. It is plausible that a lipophlilic molecule could become "trapped" in the friendly environment of the bilayer but I doubt that it would remain there for long since so much of that environment is changing around it. Those changes might, I gather, force it to depart the membrane.

This is just speculation on my part from what I understand but others may chime in. It's an interesting theoretical question, the answer to which probably involves a very elegant statistical model.