"If you cannot stand the lipophilia, get out of the nanotube"- Anon
Yes. And this sort of ties in with the recent discussions of water in hydrophobic channels and cavities that I have been reading , discussions that can have a direct impact on ligand design (and also "rational" drug design). At least in once case, a simulation of water inside a carbon nanotube, the authors find that water does indeed get inside this greasy den. This study if part of many recent studies which I believe challenge our basic notions of "hydrophobicity" of surfaces and cavities.
I was not aware of this CNT paper, which was published in Nature in 2001 (Nature | Vol 414 | 8 November 2001 | pg. 188-190). The paper involved simulating water around a CNT. The researchers found that a few water molecules do enter the CNT in single file and exit, as the CNT is wide enough to accomodate only the diameter of a water. The interesting explanation for why the waters can ever get inside such an unwelcome environment is given by the energetics; apparently the waters can form two hydrogen bonds inside the nanotube, but fluctuations in the number of hydrogen bonds even in bulk means that they are incompletely hydrogen bonded even in bulk. Part of the explanation also may be that the Hbonds inside the tube have better geometrical characteristics, although I am not sure how much enthalpic advantage such slight changes in geometry provide to a Hbond.
This is a very significant fact in my opinion, and does not completely tie in with the study of Friesner et al. where they say that expelling a water molecule from a protein cavity into bulk may be enthalpically favourable because in bulk water is assumed to form its full complement of hydrogen bonds. I think the verdict may be still out there, as far as the enthalpic gain of waters expelled from hydrophobic protein active sites is concerned. On the other hand, in the nanotube study, it's clear that since the waters are certainly entropically constrained inside the tube, which means that the enthalpic advantage is what drives them in, even if they don't stay there forever.
However, the flags which are always raised in my mind when I read such a study pertain to the method dependence of the results. After all, any model is as good as the parameters in it. For example, the very reason why people do simulations of water under confinement is because they cannot study it by experiment, but at the same time, they are using bulk or gas phase parameters to represent the water molecules. In this study, the authors use Bill Jorgensen's TIP3P water model, which is a very good model that nonetheless represents bulk and gas-phase properties. The fact that the simulation results depend on model parametrization becomes clear when the authors change the depth of the energy well of the Lennard-Jones potential by a mere 0.05 kcal/mol, they observe a drastic change in the wetting event, with a two-step wetting-dewetting transition in a a nanosecond. The question arises is; what if they had used another value for the well depth? Would they have then observed no wetting at all? And would this then have been a representation of the real world? As usual, the question here is of the transferability of parameters, in this case whether the parameters from bulk apply under confinement. Unless there is a better hypothesis and reason, there may be some good reason to believe this transferability, but as usual, with what confidence does the model represent the "real world" is another question.
On a related note, is anyone aware of studies in which such confined-water parameters have been experimentally obtained?