Effects of confinement

I have been feeling guilty at the slow pace with which I’ve been reading through a very nice preprint sent to me some time ago by Bob Eisenberg at Rush University Medical Center in Chicago, on the topic of how bubbles might act to gate ion channels. This brings together many recent ideas on how protein channels might be gated by evacuation of water from a hydrophobic pore – exactly the sort of thing discussed in the reviews by Gerhard Hummer et al. and Haiping Fang et al. in my previous post. The notion is that different channels have different mechanisms – mechanical, say, or voltage-depedent – to modulate the hydrophobicity of the channel and thus to cause an abrupt transition to a dewetted, capillary-evaporated state in which solutes are precluded from the channel. Eisenberg and colleagues present a general thermodynamic analysis of this process, and also offer the hypothesis that such a ‘bubble-induced’ mechanism might explain the anaesthetic effects of inert gases. The point is that the authors have now published the paper – or at least, what I assume is the same paper, as I’ve only so far seen the abstract – in Biophys. J. 94, 4282-4298 (2008) (paper here). Well worth looking at.

On the same general topic, Niharendu Choudhury in Mumbai has used MD simulations to look at how dewetting and capillary evaporation between two hydrophobic plates (close-packed paraffin monolayers) depends on the fine details of the plate structure (J. Phys. Chem. B 112, 6296-6300; 2008 – paper here). Specifically, he examines how the behaviour of the nano-confined water layer depends not only on plate separation but on the intermolecular distance in the paraffin plates, allowing a kind of ‘dilution’ of the hydrophobicity and solvent-surface dispersion forces. He finds that tuning this parameter can cause switches between wet, dry and intermittent wet/dry states, which might help to resolve differences seen in previous studies of this geometry. Moreover, the flickering formation and break-up of a water layer in the intermittent state can happen on nanosecond timescales, implying that simulations of protein hydration lasting only a few picoseconds may overlook important dynamical aspects of the problem.

Tobias Cramer at the University of Bologna and colleagues have looked at what one might consider the complementary problem: the spontaneous formation of a water bridge between two proximal surfaces (Langmuir 10.1021/la800220r – paper here). Their MD simulations examine how this process depends on an electric field across the gap, showing that there is a critical field strength at which the inhibitory influence of surface tension is overcome by electrostatic pressure. The focus here is mostly on scanning-probe-microscope-based experiments and technologies such as dip-pen nanolithography, but one can presumably imagine charging mechanisms for drawing water columns inside otherwise hydrophobic cavities in biomolecules. I have no idea whether such things are observed in nature…

There’s another take on nanoconfined water in a paper by Matthew Lane and colleagues at Sandia (J. M. D. Lane et al., Langmuir 24, 5209-5212; 2008 – paper here). They study the dynamics of a very thin film of water (submonolayer to bilayer) between two carboxyl-terminated alkanethiol self-assembled monolayers, using MD simulations. The diffusion coefficient of the water decreases as the layers become thinner, down to two orders of magnitude less than the bulk value, but the water remains liquid-like.

David Chandler, working with Adam Willard, has more on the role of solvent fluctuations in his dewetting model of hydrophobic assembly (discussed in earlier posts) in a paper in J. Phys. Chem. B 112, 6187-6192; 2008 (paper here). Fluctuations play a crucial role in the formation of a ‘vapour tunnel’ between two spherical hydrophobic particles, which draws them together. And in the same volume, Peter Rossky and colleagues expand on their work on the mechanism of protein cold denaturation, which I’ve also mentioned previously (C. F. Lopez et al., J. Phys. Chem. B 112, 5961-5967; 2008 – paper here).

Here’s another nice example of bound water playing a crucial role in enzyme function in a paper by Sason Shaik at the Hebrew University of Jerusalem and colleagues (Y. Wang et al., JACS 10.1021/ja711426y). They have looked at the mechanism by which cytochrome P450 StaP catalyses the formation of staurosporine, an antitumour agent, from chromopyrrolic acid. A critical step in this process is the abstraction of a proton from an N-H group on the substrate by an iron-oxo species in the enzyme. This seems to happen with the concerted assistance of two water molecules in the binding site: one shifts the proton onto a nearby histidine residue, and the other takes a proton from the other side of this residue’s side-chain and puts it on the iron-oxo group. Thus, the water molecules here form a hydrogen-bonded proton-relay network.

Rohit Pappu and colleagues at the University of St Louis in Missouri have an interesting study on the conformation of intrinsically disordered proteins, a class of protein that lack well defined 3D structures (H. T. Tran et al., JACS 10.1021/ja710446s – paper here). The common notion seems to be that because these proteins have sequences of low hydrophobicity, they are not tightly bound into compact structures by hydrophobic interactions. But IDPs are not totally random – they do have an ensemble of preferred conformational states. What creates them? The authors use simulations to conclude that these states are not dominated by specific intramolecular interactions in the polypeptide backbone, but from solvent-solute interactions, since water seems to be a generically poor solvent even for these low-hydrophobicity backbones.

More on hydration of poorly folded proteins comes from Supid Chakraborty and Sanjoy Bandyopadhyay at the Indian Institute of Technology in Kharagpur. They have used simulations to look at how the unfolding of the HP-36 subdomain of villin headpiece protein affects the dynamics of the hydration shell (J. Phys. Chem. B 112, 6500-6507; 2008 – paper here). Unfolding turns out to have a strong but quite complex effect on the rotational and translational motions of water in the hydration shell. It seems possible that there are knock-on effects: as one part of the protein unfolds, this can alter the structure and dynamics of hydration water around other segments in a cooperative manner. There’s clearly much more to be done on this interesting but under-investigated issue.

There’s more, as ever, to come when time permits…