 And yet there is something nagging here. I'm going to keep coming back to that isolated charge, plus one charge that I need to put here in vacuum. That would cost 17 kcal or so between 50 and 20. And I know I'm going to, both I and others will keep inventing this magic translocon. It will fall down on us. Magic happens in the translocon. Of course, we don't have to go from A to C. That would be expensive. We go from A to B to C. That might make sense, but there is something deeply troubling here that one of the most famous physicists in the world have noticed. And that physicist is Homer Simpson. There is a favorite episode in Homer Simpson when it tells his daughter, Lisa, young lady in this household, we obey the laws of thermodynamics. And we do so in my class too. The problem is that the laws of thermodynamics tell you that you can't destroy or create energy. So that when you go from A to C, the only thing that can matter for the thermodynamics equilibrium is what the relative energies are. It does not matter whether you take the left or the right stare together. And in particular, that means that if a helix is not really stable in the membrane, putting it through one or 5,000 translocons is not going to change that. It will still not be stable. That potentially leads to some interesting questions and maybe some very deep results. So most proteins will be quite happy in the membrane. But assuming that I have that arginine helix, why doesn't this slide just a little bit out? Well, in theory, maybe it could. But what would happen here is that I would now expose the end of the helix where we have unpaired hydrogen bonds to the interior of the membrane. That's going to be costly. I could do the same thing for polylucine or something there. The driving force would likely not be particularly strong to pull it out, but I would have the same problem here. I can't really pull something out because it's anchored in the head group regions. And if you have a tryptophan or something, this effect is even stronger. So in general, it's true we have this situation that membrane proteins are 99% hydrophobic. But when it comes to these handful of residues that are exceptions, it might actually be that a few of them might not formally be stable in the membrane, in the sense of thermodynamic stability if you wait an infinitely long time. But they are perhaps merely kinetically stable, that the translocan has forced them into this position. Now that we are in this position, just short, technically it would be cheaper to move it out here. But then I would have to go over an energy barrier that is so high that that would take 100 years before it happens. Essentially a kinetic stability. And of course in 100 years I'll be dead so I don't really care. For all intents and purposes, I would be stable anyway. It's just an interesting thought and an active area of research. We don't really know it, but remember that in general, hydrophobicity fully explains insertion.