Inside chaperonins, and dewetting for amyloids

If I were ever to do something as tendentious as deciding on a ‘paper of the week’, on this occasion it would be this one. Vijay Pande and colleagues at Stanford argue here that water trapped inside barrel-shaped enzymes called chaperonins could be crucial to the way they help proteins to fold (J. L. England et al., JACS doi:10.1021/ja802248m). This encapsulated water has generally been neglected previously. When the chaperonin complex GroEL+ES takes in an unfolded protein, it undergoes a conformational change to expose hydrophilic residues on its inner surface. Using MD simulations, Pande and colleagues show that this can be explained as a way of sequestering water in the cavity, which creates a stronger driving force for folding driven by hydrophobic interactions. Cavity hydrophilicity turns out to be well correlated with refolding rate, and fine differences found for various GroEL mutants can be explained on the basis of different spatial distributions of charged residues. The message is that this enzyme seems to mould the solvent micro-environment to favour folding in a generic way.

Joan-Emma Shea at UCSB and coworkers have teamed up with Bruce Berne, Ruhong Zhou and Lan Hua at Columbia to extend the latter group’s investigations of dewetting transitions in protein aggregation and folding to amyloids (M. G. Krone et al., JACS 130, 11066-11072; 2008 – paper here). They look at the formation of protofilaments from two parallel beta-sheets of segments of the Alzheimer amyloid-beta. Dewetting occurs in some but not all of the simulation trajectories – when it doesn’t, hydrophobic collapse is simultaneous with the expulsion of water from between the hydrophobic faces of the peptides. Dewetting always occurs when the van der Waals forces between the proteins and water are turned off, suggesting that these attractions may in reality be often sufficient to compensate for the loss of hydrogen-bonding in the confined water. Small changes in the simulation temperature can also tip the balance, suggesting both that the results of simulations like this may be highly sensitive to the nature of the molecular force fields used and also, I guess, that the balance between dewetting or not may be rather finely balanced in vitro/vivo as well as in silico.

More on the hydrophobic gap: Mark Schlossman at the University of Illinois at Chicago and colleagues have used X-ray reflectivity to probe the oil-water interface, both for heptane and for the extreme superhydrophobic case of perfluorohexane (K. Kashimoto et al., Phys. Rev. Lett. 101, 076102; 2008 – paper here). In both cases they find that any vapour-like depletion layer can be no thicker than 0.2 Å. It seems the evidence is now fairly overwhelming that a single hydrophobic surface in water is not in any meaningful sense ‘dry’.

Aggrecan, a proteoglycan with a ‘bottle-brush’ structure that is involved in the organization of the extracellular matrix of cartilage, seems to be extremely insensitive to salt, according to scattering experiments (SANS, SAXS, light) by Ferenc Horkay at NIH and colleagues (Phys. Rev. Lett. 101, 068301; 2008 – paper here). They find that the aggregation properties are very insensitive to calcium concentrations. This seems to be a necessary consequence of its biological role: aggrecan assemblies not only protect bone surfaces from wear and lubricate joints but also seem to provide a reservoir of calcium ions for bone mineralization. It’s interesting that nature could find a way of engineering such salt-independent properties into a polyelectrolyte – achieved, apparently, by virtue of the rigidity conferred by the side-chains.

I have tended naively to assume that we knew already all that needed to be known about the differences between heavy and light water. Clearly that isn’t so. Alan Soper and Chris Benmore use X-ray and neutron diffraction and simulation to refine the differences, and say that they have been underestimated. The OH bind length in water is longer than OD by about 3 percent, while the H-bond is about 4 percent shorter – making the H-O---H bond more symmetric than O-D---O (Phys. Rev. Lett. 101, 065502: 2008 – paper here).

Sony Joseph and Narayana Alura at the University of Illinois at Urbana-Champaign say that using electric fields to orient the dipoles of water molecules inside carbon nanotubes introduces a coupling between rotational and translational motions that creates a directional bias for diffusion, which can be used to pump the molecules through the tube (Phys. Rev. Lett. 101, 064502; 2008 – paper here). This is intriguing, although it seems to me that basically much the same result as was reported last year by Haiping Fang and colleagues (X. Gong et al., Nature Naotechnology 2, 709-712; 2008 – paper here).

Urban Johanson at Lund and coworkers have just published a high-resolution crystal structure of human aquaporin 5, with a fine view of the central pore (R. Horsefield et al., PNAS doi:10.1073/pnas.0801466105 – no link available yet). In contrast to other aquaporins, here the passage of gas molecules and ions seems to be prevented by a lipid occluding the central pore.

Bert de Groot at Göttingen has done a lot of work on the transport mechanism of aquaporins, and now he and coworkers have looked at the generic mechanism of ion permeation and gating in narrow peptide channels (G. Portella et al., Biophys. J. 95, 2275-2282; 2008 – paper here). I only have the abstract of this paper, but it appears they find that the free-energy barrier for ion permeation is predominantly entropic, arising from constraints on motion within the channels, rather than from the enthalpic cost of desolvation.