A nice Christmas package

There are some important and provocative papers in this batch…

Teresa Head-Gordon and her coworkers have extended their recent work on quasi-elastic neutron scattering in peptide hydration shells (e.g. Russo et al., J. Phys. Chem. B 108, 19885 and 109, 12966 (2005); Russo et al., Biophys. J. 86, 1852 (2004)) by using MD simulations to explore the way in which the hydration dynamics are affected by the heterogeneous, amphiphilic nature of most protein surfaces (M. E. Johnson et al., J. Phys. Chem. B doi:10.1021/jp806183v – paper here). The notion they proposed earlier is that the dynamics are most perturbed at the interfaces of hydrophobic and hydrophilic patches, due to the frustration created by different styles of hydration in the adjacent regimes. This now seems to be borne out by the simulations, where the water dynamics seen experimentally are reproduced for an amphiphilic peptide but not a hydrophilic one. The strongest dynamical perturbations are found for the first hydration shell of hydrophobic residues.

Jeetain Mittal and Gerhard Hummer have used simulations to try to clarify exactly what goes on at the interface of a hydrophobic surface and water (PNAS doi:10.1073/pnas.0809029105 – paper here). They are in particular examining the vexed question of whether there is a depletion layer in water density close to the surface, as proposed first by Frank Stillinger and invoked in the Lum-Chandler-Weeks model of dewetting-induced hydrophobic collapse (K. Lum, D. Chandler & J. D. Weeks, J. Phys. Chem. B 103, 4570; 1999). Experiments have now shown some evidence for a depletion layer perhaps 1-2 Å thick. But is there a sharp transition between a liquid-like and vapour-like phase, or a gradual thinning? In the former case, capillary waves are expected to blur the interface, so it’s hard to tell the difference. Mittal and Hummer find, for a purely repulsive spherical solute particle, that the interface is indeed rather sharp, but broadened by capillary waves in line with what theory predicts for a free air-water interface. The ‘dry’ layer looks to be instantaneously about 2 Å or so thick. The result is a flickering interface with patches that are intermittently dry and wet (in proportions that depend on the solute size), and transitions between them that are slow on a molecular timescale. This is all very illuminating, but I’m hard to satisfy – what happens when van der Waals forces between solvent and surface are included, I wonder?

Roland Netz at the TU Munich and his colleagues have also explored the depletion-layer problem from a very different angle. They have used MD simulations to examine how the slip length for water flow past a hydrophobic surface depends on the contact angle (D. M. Huang et al., Phys. Rev. Lett. 101, 226101; 2008 – paper here). Experimental studies in this area have given confusing and conflicting results, with slip lengths orders of magnitude different for surfaces that seem very similar. But the simulations show a rather systematic (though nonlinear) dependence of slip length on static contact angle. Moreover, they see depletion layers of molecular dimensions, whose average width varies with the ¼ power of the slip length. Thus, anything that influences the width of the depletion layer (dissolved gases) should have a marked effect on the slip length.

I referred recently to a study that challenged the notion of a dynamical transition for protein hydration water at 220 K and its interpretation as a fragile-to-strong crossover (S. Khodadadi et al., J. Phys. Chem. B 112, 14273-14280; 2008). Now here comes another one, from Michael Vogel at the Technical University of Damstadt (Phys. Rev. Lett. 101, 225701; 2008 – paper here). He has used deuterium NMR to study reorientational dynamics of hydration water for elastin and collagen, and sees no sign of a transition at 225 K. There is one at 200 K, but Vogel says that it corresponds to the onset, at lower temperatures, of thermally activated jumps in tetrahedral coordination, perhaps related to defect motion in the hydrogen-bonded network.

Fabio Sterpone and colleagues in Rome argue that the thermostability of proteins is primarily determined by protein-water interactions, with the intra-chain interactions between packed portions of the polypeptide being of only secondary importance (F. Sterpone et al., J. Phys. Chem. B doi:10.1021/jp805199c – paper here). They looked, using simulations, at the thermal stability and flexibility of three homologous proteins – one mesophilic, one thermophilic, and one hyperthermophilic. As thermal stability increases, so the proteins seem to be encased in an increasingly persistent hydration shell linked by hydrogen bonds. The idea, crudely speaking, seems to be that this shell supplies an increasingly robust protective coat against the penetration of water into the folded protein.

At the recent Hangzhou workshop I heard about the work of Shengfu Chen of Zhejiang University and colleagues on anti-fouling films that incorporate heterogeneously charged peptides. The idea is that the ability of these films to resist non-specific protein adsorption is linked to the nature of hydration of the surface chemical groups: the ‘more’ hydration there is, the stronger the disrupting influence of an incoming adsorbate and thus the more its attachment is inhibited. Shengfu and his workers in Washington and Taiwan develop this idea in a paper here (J. Phys. Chem. B doi:10.1021/jp8065713). They introduce a method for deducing the number of water molecules hydrating a given solute, and find that the greater the ‘hydration capacity’ of a solute, the greater its ability to resist protein adsorption in anti-fouling films.

Haiping Fang, my co-chair at that meeting, has an intriguing paper on the effect on water flux through a nanotube on the nature of the ‘outside structure’, in this case meaning whether the nanotube threads through a single, double or multiple sheets of graphene (X. Gong et al., Phys. Rev. Lett. 101, 257801; 2008 - paper here). In simulations, they find that the flux of water can be quite different in the various cases. For example, with two graphene sheets separated by a vacuum, the flux and flow both increases as the separation increases. And if water surrounds the nanotube in the space(s) between sheets, the flux is lowered. They deduce that interactions between water molecules inside the nanotube and the species outside the tube are responsible for the differences, emphasizing how sensitive, in this confined geometry with more or less single-file molecular traffic (where molecular motions are strongly correlated), the water transport is to the internal configurations of water molecules.

It seems clear that nanobubbles can form on hydrophobic surfaces, and very likely that these play a key role in the long-ranged hydrophobic interaction that is sometimes observed between such surfaces. The question has remained of how such bubbles, with a very high radius of curvature, can be stable when that curvature creates a large Laplace pressure which should lead to rapid diffusive efflux of gas out of the bubble. Michael Brenner and Detlef Lohse have considered this question (Phys. Rev. Lett. 101, 214505; 2008 – paper here). They say that the outflux can be balanced by an enhanced influx of gas at the contact line of bubble and surface, owing to the attraction of dissolved gas to the hydrophobic surface. They acknowledge that this is a non-equilibrium situation which suggests that in the long term the bubbles should disappear. But there haven’t yet been any long-term studies of closed systems to see whether that is the case.

Apparently sobering news from Michael Levitt and colleagues: MD simulations for protein structure refinement perform worse in explicit solvent than implicit solvent (G. Chopra et al., PNAS doi:10.1073/pnas.0810818105 – paper here). This seems to be because the potential in explicit solvent is more rugged, and so there is more chance of getting stuck in local minima unless the simulation is very long. So there are some situations in which it is still best not to consider the hydration shell molecule by molecule.

Angel Garcia at RPI and coworkers have calculated the stability diagram of the well-studied Trp-cage miniprotein (D. Paschek et al., PNAS 105, 17754; 2008 – paper here). They derive some insights into the role of hydration in pressure-induced denaturation, which they link in part to tighter packing of water around nonpolar atoms as pressure increases.

The debate over the ‘pH’ of the air-water interface continues. First-principles empirical-valence-bond calculations by Greg Voth and colleagues seem to indicate that the preference of hydrated protons for the surface (as claimed in their earlier work) is energetically (rather than entropically) promoted, due to the amphiphilic nature of the hydrated proton (S. Iuchi et al., J. Phys. Chem. B doi:10.1021/jp805304j – paper here). They say that much the same applies for a water-hydrophobe interface too.

A lot about interfaces

Janamejaya Chowdhary and Branka Ladanyi at Colorado State have used MD simulations to look at the dynamics of H-bonds at a water-hydrocarbon interface (J. Phys. Chem. B ASAP doi:10.1021/jp; paper here). They find that the reorientation of the O-H bond is anisotropic, and quantify the effects of cooperativity in the dynamics.

Robert Woods and colleagues at the University of Georgia study how bound water mediates the binding of concanavalin A to its target carbohydrate ligand (R. Kadirvelraj et al., JACS ASAP; paper here). Or rather, they look at a modified ligand of the natural trisaccharide, with a hydroxylethyl side chain that may or may not displace a conserved water in binding of the natural ligand. The crystal structure reported here shows that this water is retained, though its position is distorted. This helps to explain the previous thermodynamic data on ligand specificity for Con A, showing that there is no entropic component for the synthetic ligand arising from water displacement.

Roger Tam and colleagues in Ottawa have looked at the inhibition of ice recrystallization by mono- and disaccharides (JACS ASAP; paper here). Specifically, they look for correlates of ice-growth inhibition in the degree of hydration of the sugars, and find that, rather than using the total number of tightly bound water molecules, a better predictor of inhibiting ability is a hydration index in which the hydration number is divided by the molar volume. The researchers conclude that the inhibition arises from a disruption of water ‘pre-ordering’ at the ice-water interface.

Joe Zaccai and colleagues have measured water dynamics in human red blood cells using quasielastic incoherent neutron scattering (A. M. Stadler et al., JACS ASAP; paper here). In line with their previous work on E. coli, they find that most (90%) of the cell water has similar translational diffusion to the bulk, while about 10% is slower, this presumably being the water hydrating haemoglobin.

Sherwin Singer and colleagues at Ohio State have looked at the hydration dynamics of myoglobin using MD simulations (T. Li et al., J. Phys. Chem. B 10.1021/jp803042u; paper here). Specifically, they look at the time-dependent fluorescence Stokes shift after photoexcitation of the Trp-7 residue, a measure of the relaxation dynamics of the chromophore’s environment. The question is whether the water dynamics are due to constraint of the water by interactions with the protein, or whether they are controlled by the dynamics of the protein itself. This distinction should be revealed by arresting the protein in the simulations. Singer and colleagues find that doing so significantly changes the Stokes shift, suggesting that the intrinsic protein flexibility is important. They caution, however, that this does not necessarily imply that the water dynamics exhibit no intrinsic slow component of relaxation; rather, the protein and water dynamics are so intimately coupled that either slow water dynamics or slow protein dynamics (or both) could alter the Stokes shift.

Shekhar Garde and colleagues at RPI have conducted simulations of hydrophobically induced polymer collapse near to the interface with air or a hydrophobic wall (S. N. Jamadagni et al., J. Phys. Chem. B 10.1021/jp806528m – paper here here). They find that the driving force for collapse is smaller at the water-alkane interface, and all but vanishes at the air-vapour interface, where the polymer remains unfolded. They think that both the weaker hydration of the polymer and the enhanced density fluctuations of water at the interface produce faster conformational switches in the folded chain. The results throws up lots of interesting questions, most obviously of course what this implies for the conformational flexibility of two peptide chains approaching one another via the hydrophobic interaction.

Hangjun Lu and colleagues at Zhejiang Normal Univerity have looked at how an external charge of +1e near a carbon nanotube will affect the filling and emptying by water (H. Lu et al., J. Phys. Chem. B 10.1021/jp802263v – paper here here). It seems that the charge stabilizes the water-filled state when it is at the midpoint of the nanotube, but much less so if it is moved towards the ends. The implication is that this is a method that might be exploited by protein channels to control water transport via the positioning of ionized residues.

The freezing-point depression of water that hydrates phospholipid membranes has been studied using NMR by Dong-Kuk Lee at Seoul National University of Technology and coworkers (D.-K. Lee et al., Langmuir 24, 13598 (2008) – paper here). They find that water molecules still show liquid-like signatures below -20 C in bilayers, and that the freezing behaviour is depressed still further by cholesterol, a known cryoprotectant.

I have a kind of follow-up to my Chem. Rev. article in a forthcoming issue of ChemPhysChem, which has now appeared online (here). This will form part of a special issue on the subject of water at interfaces, stemming from a meeting of the DFG Forschergruppe 436 in Dortmund last summer.

Some DNA - and is the 220 K transition real?

At the end of October I had the pleasure of chairing the workshop on Water at Biological Interfaces in Hangzhou, China. It was a truly enjoyable and satisfying experience. Thanks to everyone who participated, and especially to the hosts at Zhejiang University and in Shanghai.

Happily, the papers have not been proliferating too rapidly while I was away…

Thomas Truskett at Texas at Austin and his colleagues have taken another look at the ‘hydrophobic collapse’ of polymers posited by Lum, Chandler and Weeks (G. Goel et al., J. Phys. Chem. B 112, 13193-13196; 2008 – paper here). They have used MD simulations of simple bead-spring polymers in water to probe how polymer collapse dependson the strength of van der Waals attractions. Provided that these are not too strong, they seem to have rather little influence on the potential of mean force for polymer collapse that arises from putative dewetting ‘cavity’ effects.

Alessandro Paciaroni of the Università degli Studi di Perugia and colleagues say that the low-energy vibrational mode density of states of the hydration water of maltose binding protein at 100 K are similar to those of amorphous ice, and quite different from crystalline ice (A. Paciaroni et al., Phys. Rev. Lett. 101, 148104; 2008 – paper here).

A potential to describe interactions between two hydrophobes that posits two minima – one for direct contacts, the other for an intervening water layer – seems empirically to work well in protein structure prediction. But why? Florin Despa and Stephen Berry have studied this question for the model case of methane (Biophys. J. 95, 4241; 2008 – paper here). They say that the ‘water-mediated’ minimum can be understood as the interaction of dipoles on the methane molecules induced by the (oriented) water layer.

Joe Dzubiella at TU Munich has looked at the effects of salt bridge on the conformation of a short, helical alanine-based peptide, rationalizing the denaturing effects of NaCl and NaI in terms of ion binding to specific residues and changes in hydration (JACS doi:10.1021/ja805562g – paper here).

Kristina Furse and Steven Corcelli at the University of Notre Dame have looked at the question of why the dynamics of probe molecules (e.g. fluorescent) at the interface of water with proteins or DNA seem to be significantly slower than those in bulk aqueous solution (JACS doi:10.1021/ja803728g – paper here). The issue is whether this slowing is dominated by changes in solvation water dynamics or by the dynamics of the biomolecules. The MD studies reported here, for the fluorescent probe molecule Hoescht 33258 bound to DNA, support the latter interpretation.

More on the roles of water bound in the active sites of enzymes on their catalytic mechanism. Yanli Wang and Tamar Schlick of New York University look at a DNA polymerase Dpo4, where a crucial deprotonation step seems to be mediated by two bridging water molecules (JACS 130, 13240-13250; 2008 – paper here).

Takeshi Yamazaki at the National Institute for Nanotechnology in Edmonton, Canada, and his colleagues have looked at the role of hydration in the formation of amyloid aggregates (Biophys. J. 95, 4540-4548; 2008 – paper here). This is a topic starting to attract a considerable amount of attention, as I’ve mentioned earlier. Yamazaki and colleagues say that there is a large entropic driving force to aggregation stemming from hydration, which they say implicates hydrophobic cooperativity as a dominant factor. I’ve only seen the abstract for this.

Alexei Sokolov at the University of Akron and his coworkers have combined dielectric spectroscopy and neutron scattering to probe the hydration dynamics of hydrated lysozyme powder between 180 and 300 K (S. Khodadadi et al., J. Phys. Chem. B 112, 14273-14280; 2008 – paper here). They see a smooth, super-Arrhenius relaxation for both the protein and its hydration shell across this entire temperature range, with no anomaly at around 220 K, which challenges the interpretation of this anomaly by S.-H. Chen and colleagues as a fragile-to-strong crossover. Rather, they think this apparent anomaly is just an artefact of the protein dynamics reaching the resolution limit of neutron spectrometry. That seems destined to provoke debate.

Jim Hynes and Damien Laage have extended their previous analysis in Science (311, 832; 2006) of the molecular reorientation mechanism of pure water (Laage & Hynes, J. Phys. Chem. B 112, 14230-14242; 2008 – paper here). They argue that the reorientation has only a small diffusive component, and occurs mostly through large-angle jumps prompted by H-bond rearrangements. The rate-limiting step is not the breaking of the H-bond itself, but the translational motion and bond elongation involved in the departure of the ‘old’ partner and the arrival of the ‘new’ one.

A curious but interesting paper by Julia Berashevich and Tapash Chakraborty of the University of Manitoba examines the influence of hydration water on the electrical and magnetic properties of DNA, mostly with an eye on the implications for DNA-based spintronic devices (J. Phys. Chem. B 112, 14083-14089; 2008 – paper here). H-bonding of the bases to water molecules creates unbound pi electrons which can contribute to conductance, and the spin-spin interactions of unbound electron pairs can result in a magnetic-field dependence of conductance.

Pores, membranes, and knots

Nikolai Ivashin of the Institute of Physics in Minsk, Belarus, and Sven Larsson at Chalmers University in Sweden have investigated the role of an interstitial water molecule (water-A) in the primary charge-separation process of a bacterial photosynthetic reaction centre (J. Phys. Chem. B 112, 12124-12133; 2008 – paper here). It seems that water-A donates a proton to a side-chain group, and receives one from another, during the photoexcitation process, stabilizing the charge-transfer state. Water-A cannot rotate in the ground state, but this becomes possible in the photoexcited state – but if I read this rightly, it’s not clear that this is an essential part of the process.

Robert Harrison and coworkers at Georgia State University have compared the radial distribution functions of hydration water molecules from 105 protein crystal structures with that of bulk water (X. Chen et al., J. Phys. Chem. B 112, 12073-12080; 2008 – paper here). The two differ, but actually not by very much: the first and second maxima are sharper for hydration water, but appear at much the same separations. Certainly, the hydration-water rdfs are not ice-like.

Tetsuo Okada of the Tokyo Institute of Technology and coworkers have used XAFS to investigate the hydration structure of alkali metal cations and of bromide in aqueous solution and in a solution of ovalbumin (T. Ohki et al. J. Phys. Chem. B 112, 11863-11867; 2008 – paper here). They find little difference between the two cases, and conclude that the positive free energy of transferring the ions from water to the protein solution comes from perturbations only of the second hydration shell and/or beyond.

Chang Won and N. R. Aluru of the University of Illinois at Urbana-Champaign have studied water inside the nanoscale channels of boron nitride nanotubes (JACS 10.1021/ja803245d – paper here). Their simulations show that formation of a Stone-Wales defect in the wall structure – basically the conversion of four adjoining hexagons into two pentagons and two heptagons – will trigger the severing of a hydrogen-bonded chain of water molecules through a narrow tube (0.69 nm width) and create a vapour-like bubble localized at the defect, reducing water transport through the tube. This is further evidence of the acute sensitivity of water transport in these nanoscale pores to small perturbations (and thus the possibility of gated flow).

In a preprint shortly to be published in J. Phys. Chem. B, Valeria Molinero and Emily Moore of the University of Utah say that water can usefully be treated as an element intermediate between carbon and silicon (paper here). This somewhat rough and ready ‘monatomic’ water model does a surprisingly good job of capturing many of the key properties, and should supply a computationally cheap coarse-grained description for simulations.

Ulrich Schmidt and colleagues at the German Cancer Research Centre in Heidelberg show how ‘hydrophobic mismatching’ – a difference in the thickness of a membrane protein’s transmembrane hydrophobic domain and the thickness of the membrane itself – can facilitate the non-specific clustering of membrane proteins commonly found in vivo (U. Schmidt et al., Phys. Rev. Lett. 101, 128104; 2008 - paper here).

There is an interesting set of papers in the latest Faraday Discussions. Especially,
James Beattie and colleagues weigh in to the debate on the acid/base nature of interfacial water by reporting that zeta potential measurements show the air-water interface to be basic (Faraday Discuss. doi:10.1039/b805266b; paper here). They say that they see the same behaviour at all inert hydrophobic interfaces.

Francois-Xavier Coudert and colleagues report Monte Carlo simulations of water droplets confined in the nanoscale channels of zeolites (Faraday Discuss. doi:10.1039/b804992k; paper here). In hydrophobic pores the water leaves few dangling OH groups, while in hydrophilic pores it opens up to form weak hydrogen bonds with the zeolite oxygens.

And Maria Ricci and her colleagues argue that confined water shows similarities to supercooled water, in particular a shortening of hydrogen bonds
(M. A. Ricci et al., Faraday Discuss. doi:10.1039/b805706k; paper here).

In reference to the Beattie paper above, Greg Voth and colleagues further the contrary view, using the empirical valence-bond model, that hydrated protons are preferentially segregated at water-hydrophobic interfaces (S. Iuchi et al., J. Phys. Chem. B doi:10.1021/jp805304j; paper here). I confess that I am not optimistic about finding some reconciliation of all this in the near future, but I hope someone will.

Jeremy England and Vijay Pande have expanded on their recent JACS letter investigating the way water may be organized inside chaperonins, supporting the view that the cavity of GroEL may create a microenvironment that enhances the hydrophobic effect (Biophys. J. 95, 3391-3399; 2008 – paper here).

Andrew McCammon and colleagues at UC San Diego have looked at the thermodynamics of lipid partitioning between membranes and solution (A. A. Gorfe et al., Biophys. J. 95, 3269-3277; 2008 – paper here). They conclude that the hydrophobic effect here is primarily enthalpy-driven.

Joe Dzubiella at TU Munich has an interesting preprint) describing how a protein knot might trap a water molecule – I’ve discussed this and related work in my column in the October issue of Nature Materials.

Are nanopipes more slippery?

Several recent papers have shown both theoretically and experimentally that water flows through nanopipes (such as carbon nanotubes) more quickly than would be expected by extrapolating normal macroscopic pipe flow to the nanoscale (see, for example, J. C. Rasaiah et al., Ann. Rev. Phys. Chem. 59, 713-740; 2008). This, along with the exclusion of ions from very narrow pores, has raised hopes that nanotube membranes might be used for efficient desalination. One day New Scientist is going to publish a feature from me on this, but they have been sitting on it for months (as is their wont). Now Nick Quirke at Imperial College in London and colleagues have found enhanced transport, by a factor of up to 45, for water and other liquids (ethanol, decane) through wider carbon nanotubes than studied previously (M. Whitby et al., Nano Lett. 8, 2632-2637; 2008 - paper here). The reasons are not yet fully understood, but are likely to depend on the specifics of the fluid-wall interaction. This doesn’t obviously help much with desalination, but bodes well for ultrafiltration.

But John Thomas and Alan McGaughey at Carnegie Mellon sound a warning bell. Their MD simulations (J. A. Thomas & A. J. H. McGaughey, Nano Lett. 8, 2788-2793; 2008 – paper here) find significantly lower flow enhancement than reported previously in experiments (e.g. Holt et al., Science 312, 1034-1037; 2006; Majumder et al., Nature 438, 44; 2005). Thomas and McGaughey suggest that the experiments might have miscalculated the true flow area, or might have been affected by external driving forces such as electric fields.

Two papers this week probe the nature of nanoconfined water. Manu Sharma, Giulia Galli at UC Davis and their coworkers have calculated theab initio IR spectra of confined water, and say that some of the features seen experimentally are due to electronic charge fluctuations at the interface (M. Sharma et al., Nano Lett. 8, 2959-2962; 2008 – paper here). They also suggest that the frequency shifts of some spectral peaks relative to the bulk are due to confinement-induced changes in the hydrogen-bond network. And Jean Philippe Renault at CEA Laboratory of Radiolysis in Gif-sur-Yvette and colleagues use pump-probe IR spectroscopy to look at those effects on hydrogen bonds for water in porous glasses (I assume silica) with pores of 1, 13 and 50nm width (R. Musat et al., Angew. Chem. Int. Ed. doi:10.1002/anie.200802630; paper here). There are apparently modifications of the relaxational dynamics even for the largest pores. The bottom line reiterates a familiar notion: “the microscopic properties of water are influenced by the space it occupies.”

Roland Netz and colleagues at TU Munich have studied the friction and adhesion of polypeptides on hydrophilic and hydrophobic diamond surfaces using MD simulations (A. Serr, D. Horinek & R. R. Netz, JACS 130, 12408-12413; 2008 – paper here). They find stick-slip motion due to making and breaking hydrogen bonds (with little sign of cooperativity) on the hydrophilic surface, but smooth motion on the hydrophobic one.

Getting up to date

I don’t like to do this, but a combination of holidays and a glut of papers means that, in order to have any chance of getting this blog up to date, I am going to have to provide a mere listing of relevant papers here, without further comment or explanation. I hope that the titles will speak for themselves; there is a wealth of nice stuff here. Normal service will be resumed as the days draw in.

1. PNAS advance online publication
Burst analysis spectroscopy: A versatile single-particle approach for studying distributions of protein aggregates and fluorescent assemblies
Jason Puchalla, Kelly Krantz, Robert Austin and Hays Rye
(Paper here).

2. J. Phys. Chem. B 112, 11106–11111, 2008. 10.1021/jp803956s
Hydrophobic Interactions in Urea_Trimethylamine-N-oxide Solutions
Sandip Paul and G. N. Patey
(Paper here).

3. J. Am. Chem. Soc. 10.1021/ja8021297
Interfacial structure of acidic and basic aqueous solutions
C. Tian et al.
(Paper here).

4. J. Phys. Chem. B 112, 11440-11445, 2008. 10.1021/jp803819a
Anomalously increased lifetimes of biological complexes at zero force due to the protein-water interface.
Y. V. Pereverzev et al.
(Paper here).

5. J. Phys. Chem. B 112, 11396-11401, 2008. 10.1021/jp8015886
Quantum mechanical studies of residue-specific hydrophobic interactions in p53-MDM2 binding
Y. Ding et al.
(Paper here).

6. J. Am. Chem. Soc. 130, 11854-11855, 2008. 10.1021/ja803972g
Chemical denaturants inhibit the onset of dewetting.
J. L. England et al.
(Paper here).

7. J. Am. Chem. Soc. 10.1021/ja8034027
Dual function of the hydration layer around an antifreeze protein revealed by atomistic molecular dynamics simulations.
D. R. Nutt & J. C. Smith.
(Paper here).

8. J. Phys. Chem. B 112, 10786–10790, 2008. 10.1021/jp804694u
Polarization of Water in the First Hydration Shell of K+ and Ca2+ Ions
Denis Bucher and Serdar Kuyucak
(Paper here).

9. ASAP J. Phys. Chem. B ASAP Article, 10.1021/jp802795a
Hydration Water and Bulk Water in Proteins Have Distinct Properties in Radial Distributions Calculated from 105 Atomic Resolution Crystal Structures
Xianfeng Chen, Irene Weber and Robert W. Harrison
(Paper here).

10. ASAP J. Phys. Chem. B ASAP Article, 10.1021/jp711924f
Trapped Water Molecule in the Charge Separation of a Bacterial Reaction Center
Nikolai Ivashin and Sven Larsson
(Paper here).

11. J. Am. Chem. Soc. 130, 11582–11583, 2008. 10.1021/ja803274p
Specific Ion Binding to Nonpolar Surface Patches of Proteins
Mikael Lund, Lubos_ Vrbka and Pavel Jungwirth
(Paper here).

12. J. Am. Chem. Soc. 130, 11578–11579, 2008. 10.1021/ja802341q
Dissecting Entropic Coiling and Poor Solvent Effects in Protein Collapse
Frauke Gräter, Pascal Heider, Ronen Zangi and B. J. Berne
(Paper here).

13. ASAP J. Am. Chem. Soc. ASAP Article, 10.1021/ja8022434
Electron Capture by a Hydrated Gaseous Peptide: Effects of Water on Fragmentation and Molecular Survival
James S. Prell, Jeremy T. O’Brien, Anne I. S. Holm, Ryan D. Leib, William A. Donald and Evan R. Williams
(Paper here).

14. ASAP J. Chem. Theory Comput. ASAP Article, 10.1021/ct800121e
Dissecting the Hydrogen Bond: A Quantum Monte Carlo Approach
Fabio Sterpone, Leonardo Spanu, Luca Ferraro, Sandro Sorella and Leonardo Guidoni
(Paper here).

15. J. Am. Chem. Soc. 129, 2504 -2510, 2007. 10.1021/ja0659370 S0002-7863(06)05937-3
Effect of Field Direction on Electrowetting in a Nanopore
Dusan Bratko, Christopher D. Daub, Kevin Leung and Alenka Luzar
(Paper here).

16. J. Chem. Phys. 127, 174515 (2007); DOI:10.1063/1.2784555
Investigations on the structure of dimethyl sulfoxide and acetone in aqueous solution
S. E. McLain, A. K. Soper and A. Luzar
(Paper here).

(These latter two are older ones I’ve just discovered.)

17. Faraday Discussions 141, 1-12, 2008
Water-mediated ordering of nanoparticles in an electric field
D. Bratko, C. D. Daub & A. Luzar
Not yet on the web; doi:10.1039/b809135h

18. Biophysical Journal 95, 2916-2923, 2008
Hydration Affects Both Harmonic and Anharmonic Nature of Protein Dynamics
H. Nakagawa , Y. Joti , A. Kitao and M. Kataoka
(Paper here).

19. Langmuir 24, 9183–9188, 2008. 10.1021/la8014578
Teflon is Hydrophilic. Comments on Definitions of Hydrophobic, Shear versus Tensile Hydrophobicity, and Wettability Characterization
Lichao Gao and Thomas J. McCarthy
(Paper here).

20. PNAS 105, 12725-12729, 2008
NMR evidence of a sharp change in a measure of local order in deeply supercooled confined water
F. Mallamace, C. Corsaro, M. Broccio, C. Branca, N. González-Segredo, J. Spooren, S.-H. Chen & H. E. Stanley
(Paper here).

21. PNAS 105, 13391-13396, 2008
Dehydration of main-chain amides in the final folding step of single-chain monellin revealed by time-resolved infrared spectroscopy
T. Kimura, A. Maeda, S. Nishiguchi, K. Ishimori, T. Konno, Y. Goto & S. Takahashi
(Paper here).

22. J. Chem. Phys. 129, 034504, 2008
POLIR: Polarizable, flexible, transferable water potential optimized for IR spectroscopy
P. K. Mankoo & T. Keyes
(Paper here).

23. JACS 130, 9025-9030, 2008
Combined electrostatics and hydrogen bonding determine intermolecular interactions between polyphosphoinositides
I. Levental, A. Cebers & P. A. Janmey
(Paper here).

24. J. Phys. Chem. B 112, 5500-5511, 2008
Operation of the proton wire in green fluorescent protein. A quantum dynamics simulation
O. Vendrell, R. Gelabert, M. Moreno & J. M. Lluch
(Paper here).

25. PNAS 105, 9233-9237, 2008
A stringent test for hydrophobicity scales: two proteins with 88% sequence identity but different structure and function
A. E. Kister & J. C. Phillips
(Paper here).

26. J. Phys. Chem. B 112, 9532-9539, 2008
Effect of the air-water interface on the structure of lysozyme in the presence of guanidinium chloride
A. W. Perriman, M. J. Henderson, C. R. Evenhuis, D. J. McGillivray & J. W. White
(Paper here).

27. JACS 130, 10939-10946, 2008
Hydration and conformational mechanics of single, end-tethered elastin-like polypeptides
A. Valiaev, D. W. Lim, S. Schmidler, R. L. Clark, A. Chilkoti & S. Zauscher
(Paper here).

28. J. Phys. Chem. B 112, 10158-10164, 2008
Do probe molecules influence water in confinement?
B. Baruah, L. A. Swafford, D. C. Crans & N. E. Levinger
(Paper here).

29. J. Phys. Chem. B 112, 7702-7705, 2008
Stepwise hydration of protonated proline
C. Michaux, J. Wouters, E. A. Perpète & D. Jacquemin
(Paper here).

30. J. Phys. Chem. B 112, 7157-7161, 2008
Anion fractionation and reactivity at air/water:methanol interfaces. Implications for the origin of Hofmeister effects.
J. Cheng, M. R. Hoffmann & A. J. Colussi
(Paper here).

31. J. Phys. Chem. B 112, 7810-7815, 2008
Two-particle entropy and structural ordering in liquid water
J. Zielkiewicz
(Paper here).

32. PNAS 105, 7456-7461, 2008
Entropic contributions and the influence of the hydrophobic environment in promiscuous protein-protein association
C.-E. A. Chang, W. A. McLaughlin, R. Baron, W. Wang & J. A. McCammon
(Paper here).

33. Mol. Phys. 106, 485-495, 2008
The distribution of acceptor and donor hydrogen-bonds in bulk liquid water
O. Markovitch & N. Agmon
(Paper here).

Some meeting news:
Alenka Luzar is organizing a session at Pacifichem 2010 that hits the bullseye of all the topics I try to cover here; see here.

And finally, a real oddity:
Geophys. Res. Lett. 35, L16710, doi:10.1029/2008GL034288, 2008
Magnetic effect on CO2 solubility in seawater: A possible link between geomagnetic field variations and climate
Alexander Pazur& Michael Winklhofer
(Paper here).
This looks at face value irrelevant to water in biology, except that if these weak-field effects are seen for seawater, would one not expect them for blood and cytoplasm? And in that case, would significant changes in air and CO2 solubility not be expected to have profound physiological implications? And am I therefore right to be deeply sceptical?

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.

Some new perspectives on old debates

Garegin Papoian has extended his previous studies of how water-mediated contacts influence protein folding, with a new paper with Christopher Materese and Christa Goldmon (C. K. Materese et al., PNAS doi:10.1073/pnas.0801850105 – paper here). The basic notion is that a variety of contacts in the folding peptide – hydrophobic, hydrophilic, salt bridges – are ‘tried out’ during the folding process and filtered down to a subset of preferred interactions in a hierarchical branching process. This paper shows that many of these contacts are mediated by bridging water molecules, and that subsets of such interactions are characteristic of certain basins in the folding landscape. It adds to the argument that explicit water is essential for a full picture of the folding process.

Valerie Daggett and colleagues at the University of Washington in Seattle have carried out simulations of aquaporin embedded in a lipid bilayer to study the role of protein fluctuations on water transport (N. Smolin et al., Biophys. J. 95, 1089-1098; 2008 – paper here). Their aim was to look at some of the apparent discrepancies in earlier studies of how water passes through the protein pore in a hydrogen-bonded wire (e.g. Tajkhorshid et al., Science 296, 525-530; 2002; de Greet & Grubmuller, Science 294, 2353-2357; 2001). The key action seems to happen in the narrow constriction at the centre of the channel called the NPA region. Here, the dynamics of two asparagine residues seem to play a crucial role in aligning the water molecules for transport to occur. But beyond the constriction is a ‘valve’ region in which two residues, His76 and Val155, act to control the flow by potentially swinging into the channel to block the passage of the water molecules. The emerging picture, then, is of a remarkably orchestrated collaboration of side-chain and water dynamics to regulate the progress of the water along the ‘wire’.

H. Nagase of Hoshi University in Tokyo and his coworkers have continued their exploration of the molecular mechanisms of anhydrobiosis and how trehalose acts as a bioprotectant in this regard (H. Nagase et al., J. Phys. Chem. B. 112, 9105-9111; 2008 – paper here). They have studied the crystal structure of trehalose anhydrate, and find that it contains a one-dimensional channel threading between the trehalose molecules which may be filled with water in the dihydrate form of solid trehalose. This water uptake facilitates the transformation from the anhydrate to the dihydrate, and effectively makes the crystalline form a potential source and sink of water. If I understand this rightly, I believe the idea is then that this ‘water sponge’ prevents uptake of water by the amorphous (glassy) phase of trehalose thought to be responsible for bioprotection, which would otherwise lower its glass transition temperature.

Fernando Bresme at Imperial College and his coworkers have returned to the controversial question of a ‘hydrophobic gap’ or depletion layer at the interface of water with a hydrophobic surface (Phys. Rev. Lett. 101, 056102; 2008 – paper here). They model this interface as that between water and dodecane or hexane, which they study using computer simulations. Their objective is to decouple the intrinsic width and density profile of the interface with the effect of fluctuations from capillary waves, which will blur the details. They find that at 300 K water at the interface resembles that at the air-water interface – despite the fact that there is no appreciable intervening vapour film because the system is far from the drying transition. And the interface is rather rigid: corrugations remain well below a molecular diameter. But the water structure is significantly perturbed, with layering similar to that seen at a hard surface. Of course, this leaves open the question of what a nanoscopic film of water looks like between two such surfaces (see below), let alone the issue of how (if at all) a more rigid hydrophobic surface changes the situation. But it does seem to support the growing consensus that any ‘hydrophobic gap’ is extremely narrow.

On the same issue, there’s an interesting exchange in Phys. Rev. Lett. between Ben Ocko and colleagues and Steve Granick and coworkers (B. Ocko et al., Phys. Rev. Lett. 101, 039601 and A. Poynor et al., 039602; 2008 – letters here and here). Poynor et al. claimed previously (Phys. Rev. Lett. 97, 266101; 2006) that they see a depletion layer 2-4 Å thick with a reduced water density of at least 40 percent of the bulk. Ocko et al. say that, if the hydrogen-rich methyl groups of the hydrophobic monolayer are taken into account, the density deficit is much reduced, and might in fact be explained instead by local water orientation. Poynor et al. reject the latter interpretation, but agree that, as they stated, their originals density depletion was cited only as an upper bound. They point out that there does now seem to be agreement that a depletion zone exists (and, I guess, that it is very narrow and certainly not gas-like), and argue that the focus now should be on the role of fluctuations in the interfacial density. David Chandler has argued that indeed it’s the fluctuations (as opposed to the average equilibrium state) that matter for any discussion of how dewetting might occur between two such surfaces.

I have been meaning for some time to mention a paper by Alexander Pertsin and Michael Grunze (Langmuir 24, 4750-4755; 2008 – paper here) on simulations of the shear behaviour of water films between hydrophilic surfaces. Perhaps the delay was fortuitous, because into this discussion there now comes an experimental paper by K. B Jinesh and Joost Frenken at Leiden (Phys. Rev. Lett. 101, 036101; 2008 – paper here). Pertsin and Grunze previously simulated water monolayers (Langmuir 24, 135; 2008 – paper here), and found that they could observe essentially solid-like configurations in the confined layer. They now say that solidification can happen for bilayers too when sheared quasi-statically (that is, with an infinitely small shear rate) – but only for a small range of wall-to-wall separation, where the separation between the two monolayers is favourable for the formation of hydrogen bonds between them. The solid-like shear behaviour also depends on the relative alignment and period of the wall lattices. And importantly, the solid-like shear behaviour does not involve film crystallization. For trilayers, there is no solid-like behaviour at all.

So then, a complex picture. Now, already this seems to complicate the picture reported by Zhu and Granick (Phys. Rev. Lett. 87, 096104; 2001), where oscillatory shear of electrolyte films between mica showed no solid-like signature. One might add that Jacob Klein and colleagues have also seen the retention of fluidity in sub-nanometre confined water films under shear (U. Raviv et al., Nature 413, 51-54; 2001). Yet Jinesh and Frenken claim to see a solid-like response in their friction-force measurements of water between a graphite surface and a tungsten tip. Specifically, they see stick-slip behaviour which seems to change, with increasing humidity, from that expected for graphite corrugation to that with a different periodicity (around 0.4 nm), similar to a lattice periodicity of ice. The film thickness here is not known for sure, but is less than about 2 nm. (I notice that they have made this claim before on the basis of different evidence, which has caused a little confusion.)

Now, I’ve seen some criticisms of this latest work – for example, that it seems to attribute thermodynamic transitions from dynamic mechanical measurements, that it ignores the possibility of surface reconstructions of bulk ice or of a tip-sample potential and the role of the lateral spring constant in the cantilever in determining the 0.4 nm periodicity. This is a tricky issue – it would be unfair to level unattributed criticisms at the work, but neither can I pretend I haven’t heard them. I guess I can only say that there seems to be a debate in store, and until that happens we might best regard the results as no more than suggestive. In any event, if Pertsin and Grunze are right, there is likely to be a great deal of further subtlety to the question, not least in terms of the lattice periodicities and the hydrophobicity/hydrophilicity of the surfaces.

Staying with fundamentals, Noam Agmon, Greg Voth and their colleagues present a new look at the details of proton transport in water – classically explained by the Grotthuss hopping mechanism but now known to be a more complex, cooperative process (O. Markovitch et al., J. Phys. Chem. B 112, 9456-9466; 2008 – paper here). Their quantum-chemical calculations offer a fine-grained picture involving a range of time and distance scales: a ‘dance’ that embraces proton motions and water reorientations in both the first and the second hydration shells of the central hydronium ion.

An interesting paper by Haoran Li and colleagues at Zhejiang University in Hangzhou (X. Hu et al., J. Phys. Chem. B doi:10.1021/jp8028903 – paper here) explores not a biologically relevant process per se – the iron-porphyrin-catalysed activation of methane and methanol – but one that has interesting parallels to the functions of some cytochromes and horseradish peroxidise. In both of those latter cases, water molecules have been found to play important roles, particularly by providing bridges for proton transport to or from the heme group. Water has also been found to assist metal-porphyrin-catalysed oxidation in trace amounts, but to suppress the reaction when present in greater amounts. Li et al. find that a water molecule near the iron porphyrin can either assist or inhibit the catalytic processes considered here, depending on where it sits.

Hydration dynamics, amyloids, and more

My pile of water-related papers is stacking up worryingly, so let me now try to clear it. Thanks again to everyone who has sent me papers – it is always a pleasure to receive them.

Roberto Senesi and Antonino Pietropaolo at Rome and their colleagues have been producing a succession of papers in which they use inelastic neutron scattering to study the momentum distributions of protons in water in a variety of settings: in nano-confined systems (G. Reiter et al., Phys. Rev. Lett. 97, 247801; 2006 – paper here; and V. Garbuio et al., J. Chem. Phys. 127, 154501; 2007 – paper here), in supercooled water (A. Pietropaolo et al., Phys. Rev. Lett. 100, 127802; 2008 – paper here) and the ambient liquid and supercritical phase (C. Pantalei et al., Phys. Rev. Lett. 100, 177801; 2008 – paper here), and in a protein hydration shell (R. Senesi & A. Pietropaolo, Phys. Rev. Lett. 98, 138102; 2007 – paper here). The last of these is of course particularly relevant here. The authors study the momentum distributions for hydration protons around lysozyme both above (290 K) and below (180 K) the dynamical transition at around 220 K. At 290 K, the results are consistent with a hydration shell that is slightly denser than bulk water, with a smaller oxygen-oxygen distance that confines the protons in a double well, with the possibility of tunnelling between minima. This suggests that tunnelling may occur even at room temperature ion the hydration shell, with potential implications for biological function. That, of course, is something that would be picked up in simulations only in a full quantum-chemical treatment.

There’s an important paper by Johan Qvist and Bertil Halle in JACS (doi:10.1021/ja802668w paper here) on rotational dynamics of water in hydrophobic hydration shells, probed by deuterium NMR. They find for four partly hydrophobic solutes, including two peptides and two osmolytes, that below 255 K hydration water rotates with a lower activation energy, and faster if the temperature is low enough, than it does in the bulk. As they say, “these findings reverse the classical ‘iceberg’ view of hydrophobic hydration by indicating that hydrophobic hydration water is less ice-like than bulk water.” It will be good to put that idea finally to rest. Moreover, the two osmolytes have opposite effects on protein stability but the same effect on water dynamics, again challenging the common view that somehow ‘water structure’ is responsible for these effects. As the authors say, “Such poetic explanations may be misleading unless they are accompanied by a precise definition of water structure. Indeed, much of the confusion in the literature stems from indiscriminate use of the word ‘structure’. Furthermore, the connection between water dynamics and structure is non-trivial.” These NMR results do, however, seem to conflict with quasi-elastic neutron scattering studies (e.g. D. Russo et al., Biophys. J. 86, 1852; 2004), and Qvist and Halle suggest some reasons for that. A final word of caution: the small peptides here serve as models for unfolded proteins, while as Qvist and Halle say, “for folded proteins, the intricate surface topography features solvent-penetrated pockets with more substantial perturbations of water dynamics than at the convex parts of the surface.”

Poul Petersen and Rick Saykally have a new contrubution to the ongoing debate over whether the air-water surface is basic or acidic (Chem. Phys. Lett. 458, 255-261; 2008 – paper here). They use resonant UV second-harmonic generation spectroscopy to study the question, and find that the results are best understood as indicating a surface depletion of hydroxide and enhancement of hydrated protons. This paper gives a nice overview of the history of this issue and the current state of play, and offers a suggestion for why the results seem to conflict with the conclusions based on macroscopic measurements of zeta potentials at bubble surfaces.

More on gating of protein channels. Carmen Domene at Oxford and coworkers report a simulation study of potassium channels in which they look at how conformational changes in the constriction responsible for ion selectivity can also induce gating by in effect snipping the hydrogen-bonded chain of water molecules (C. Domene et al. JACS doi:10.1021/ja801792g; paper here). Dirk Gillespie at Rush University Medical Center had a recent paper on the mechanism of divalent selectivity in calcium channels (Biophys. J. 94, 1169-1184; 2008 – paper here). And he and his coworkers have a new paper using synthetic nanopores to investigate a theory for the mechanism of the anomalous mole fraction effect in ion channels, whereby two types of ion produce a lower conductance than the same concentration of either ion on its own (D. Gillespie et al., Biophys. J. 95, 609-619; 2008 – paper here). They show that single-file motion of the ions through the channel is not necessary to produce this effect.

At the recent meeting of the DFG Forschergruppe 436 in Dortmund I had the pleasure of meeting Rajesh Mishra and Roland Winter, who now have an interesting paper on the issue of amyloid polymorphisms of proteins, specifically on how cold denaturation and high pressure can dissolve protein aggregates (Angew. Chem. Int. Ed. doi:10.1002/anie.200802027 – paper here). I’ve not been able to read the full paper yet, but from talking to Rajesh I can see that this is a potentially very fruitful direction.

Also forthcoming in Angewandte Chemie, though I’ve not seen it online yet, is a paper by Martin Gruebele, Martina Havenith and colleagues entitled “Real-time detection of protein-water dynamics upon folding by terahertz absorption”, which does what it says on the can (the protein here is ubiquitin). The results provide more evidence of slaving of (some) protein dynamics to solvent motions – in this case, if I understand correctly, the coupling comes from the way hydrogen bonds between the unfolded protein backbone and water are broken and then remade as intramolecular H-bonds in the secondary structure.

In a somewhat related vein, Biman Bagchi and colleagues at the Indian Institute of Science in Bangalore have studied hydrogen-bond breaking in the hydration shell of lysozyme (B. Jana et al., J. Phys. Chem. B doi:10.1021/jp800998w – paper here). They see three different mechanisms for bond-breaking. In 80 percent of cases, the new acceptor water molecule comes from within the first coordination shell, and the old acceptor water molecule remains in the shell. Neither the incoming nor the outgoing acceptor molecules show diffusive motion. In 10 percent of cases, the new acceptor comes from the second coordination shell, with the donor being in the first. In the remaining 10 percent of cases, both of the acceptor molecules are initially in the first coordination shell, but the old acceptor moves out after bond breaking. In all cases, the donor molecule undergoes a large-angle reorientational jump on making the new bond.

Alfonso De Simone in Naples (currently at Cambridge) has sent me a couple of nice reprints. In a paper in Proteins (G. Colombo et al., Proteins 70, 863-872; 2008) he and his colleagues have looked at whether amyloid-like fibrils, here of ribonuclease A, retain native-like domains. Using MD simulations, they find that this is indeed the case in these fibrils: there are segments that retain monomer-like conformations, dynamics and hydration structures, explaining why the fibrils seem to retain some catalytic activity. They also discuss how hydration changes in polyglutamine stretches might promote hydrophobic collapse leading to aggregation (despite the fact that glutamine is generally considered to be hydrophilic). Alfonso says “a better inspection showed that the huge accessibility of glutamines to sidechain-sidechain H-bonds generated a chaotic and complex network. As a result of continuous forming and breaking of sidechain-sidechain H-bonds, the water was not able to interact stably with glutamines and presented very short residence times… Therefore the message is that dewetting can be triggered even by surfaces that are able to engage in a large number of H-bonds with water. Sometimes the dynamics of the interaction are even more important than the interaction itself.”

The other paper looks at the “Role of hydration in collagen triple helix stabilization” (A. De Simone et al., Biochem. Biophys. Res. Commun. 372, 121-125; 2008). They find, again vai MD simulations, a wide range of water residence times in the hydration layer, strongly influenced by the local peptide sequence. Moreover, the stabilizing effect of Arg and Hyp (hydroxyproline) residues on the triple helix is water-mediated.

Well, that does not clear my pile but it makes a dent. More as soon as I’m able.

Hangzhou Water 08

Time, I think, for this announcement of a forthcoming meeting in China. Apologies that the web link below isn't up and running yet, but I'm sure it soon will be.

Workshop on Water at Biological Interfaces

Hangzhou Water08
Oct. 27-28, 2008, Hangzhou, China
http://www.sinap.ac.cn/water08/index.html

First Announcement & Call for papers

Hangzhou Water08 is sponsored by the Shanghai Institute of Applied Physics (SINAP), cosponsored by the Zhejiang University, Organized by Shanghai Institute of Applied Physics, Chinese Academy of Sciences, and supported by National Science Foundation of China and the Chinese Academy of Science, and Ministry of Science and Technology of the People’s Republic of China

Water at biological interfaces plays a crucial role in cell and molecular biology. It has become increasingly clear over the past two decades or so that water is not simply life’s passive solvent, but is an active and versatile matrix that engages and interacts with biomolecules in complex, subtle, and essential ways. Most dramatically, it affects the structure, dynamics, folding and unfolding, interactions and functions of proteins. Moreover, the structure and dynamics of protein hydration shells seem to feed back onto those aspects of the biomolecules themselves, so that biological function depends on a delicate interplay between what we have previously regarded as distinct entities: the molecule and its environment. A fundamental understanding of the properties of water at biological interfaces is also important for many practical issues, including environmental problems and technologies for desalination, purification and waste water recovery.

The workshop provides an excellent opportunity for researchers from different disciplines to review the latest progress on interfacial biological water, and exchange their experience, progress and ideas.

Chair: Philip Ball, Nature, 4-6 Crinan Street, London N1 9XW, U.K.
Co-Chair: Haiping Fang, Shanghai Institute of Applied Physics, CAS, Shanghai
Secretary: Shenfu Chen, Zhejiang University
Xiaoling Lei, Shanghai Institute of Applied Physics, CAS, Shanghai

Organizing Committee
1. Enge Wang, Institute of Physics, CAS, China
2. Xiangyang Liu, National University of Singapore, Singapore
3. Ruhong Zhou, IBM Watson and Columbia University, USA
4. Jichen Li, University of Manchester, UK
5. Yuhong Xu, Shanghai Jiao Tong University, China
6. Jun Hu, Shanghai Institute of Applied Physics, CAS, China
7. Fengshou Zhang, Beijing Normal University, China
8. Gang Pan, State Key Laboratory of Environment Aquatic Chemistry, CAS, China
9. Shaoping Deng, Zhejiang Gongshang University, China
10. Shenfu Chen, Zhejiang University

More Hofmeister headaches

The debate rumbles on over Hofmeister effects. In a paper in Scholarly Research Exchange [doi:10.3814/2008/761829 – paper here], Terence Evens and Randall Niedz of the US Horticultural Research Laboratory in Florida say that many previous studies of ion-specific effects on protein precipitation are flawed because they fail to take into account the dependence of pH on the type and concentration of ions in solution, treating it as an independent variable. More generally, they say that individual ion effects can’t be deduced in any straightforward way from the effects of specific salts. In a nutshell, this seems to be the key message: ‘Is the sulphate ion more effective at protein precipitation than the chloride ion? It depends on the protein. It depends on protein concentration. It depends on the concentration of the respective ions. It depends on the proportions and concentrations of the other cations and anions in solution. It depends on the dissolved gases. It may or may not depend on the pH. It depends on temperature. These dependencies are conflated, confounded, lost or ignored in traditional Hofmeister series, but are fundamentally essential to realizing a deeper understanding of ion-specific effects.’ Discuss, as they say. It’s certainly a rather discouraging message on what is already a bewildering problem, but Evens and Niedz present results for ovalbumin and BSA that seem to bear out this complexity.

In a related vein, Shekhar Garde and colleagues at RPI have examined the thermodyanmcis of hydrophobic hydration, association and folding for a hydrophobic polymer in sodium chloride solution and aqueous trimethylamine oxide (TMAO), an osmolyte [M. V. Athawale et al., J. Phys. Chem B 112, 5661; 2008 – paper here]. They’ve found previously that NaCl weakens hydrophobic hydration and enhances association, while TMAO has little effect (Ghosh et al., J. Phys. Chem. B 109, 642; 2005 and Athawale et al., Biophys. J. 89, 858; 2005). Here they carry out temperature-dependent simulations to figure out if the effects are entropic or enthalpic. For TMAO, there is almost precise enthalpic-entropic compensation. For NaCl, changes in solvent-solvent, solvent-salt and salt-salt energy lead to a dominant enthalpic contribution at small length scales (that is, for small solutes), but the strengthening of hydrophobic interactions is entropic in origin at large length scales, being governed by the need to form a solvent-solute interface. This seems to offer further evidence that there is no single ‘explanation’ of Hofmeister-type effects.

Meanwhile, Agustín Colussi and colleagues at Caltech have returned to a more basic level of the problem: the fractionation of ions at the air-water interface (a loose proxy for the air-hydrophobe interface) [J. Cheng et al., J Phys. Chem. B 112, 7157; 2008 – paper here]. They have shown previously [J. Cheng et al., J. Phys. Chem. B 110, 25598; 2006] that aggregation of anions at the interface seems to increase with increasing ion radius. They now extend their experimental study to the cases of the large anion PF6- and the highly polarizable IO3-, and look also at the effect of adding methanol, which will migrate to the surface and cap it with methyl groups. The same relationship with ion radius is found, and the fractionation barely depends on the methanol content. The authors conclude that this fractionation happens not because the ions have any affinity with the surface but because they are expelled from the bulk.

Now forget the salts. Esben Thormann and colleagues at the University of Southern Denmark have looked again at a familiar model system: a polystyrene particle several microns across stuck to an AFM tip and brought close to hydrophobic and hydrophilic surfaces [E. Thormann et al., Langmuir doi:10.1021/la8005162 – paper here]. For approaching surfaces in the hydrophilic case, all looks fine: the interactions are described by DLVO theory. But for the hydrophobic case, bridging air bubbles form, as has often been hypothesized, leading to jump-in at a separation of around 10 nm due to the action of the meniscus. When the particle is retracted, the bubble becomes elongated until it ruptures at about 70 nm. In both cases there are also force plateaus at separations of up to a few hundred nm, which the researchers interpret in terms of bridging polymer molecules pulled out from the particle surface. All this argues for caution in regarding the system as a model of the biological case.

Let’s stick with these model surfaces for a bit. Some time ago I mentioned some ‘curious’ results of Andrei Sommer and colleagues at the University of Ulm on irradiation of water films on diamond. I found some difficulty there figuring out what the underlying hypothesis was. Andrei has now sent me more material on this. The basic motivation for the work is the fact, known for some time but unexplained, that the surfaces of diamond are somewhat conductive. Andrei and colleagues believe this is due to proton migration in thin surface films of water, which are formed in humid conditions. Their experiments [A. P. Sommer et al., Cryst. Growth. Design 7, 2298; 2007] show that for hydrogen-terminated diamond, the conductivity drcreases with increasing humidity. They think this is because the highly ordered water films that form at low humidity are disrupted, degrading proton motion, as the films get thicker. This idea challenges the widely accepted model for the surface conductivity, called the transfer doping model [M. I. Landstrass & K. V. Ravi, Appl. Phys. Lett. 55, 975; 1989], which would predict increased conductivity with increased humidity. Andrei and colleagues have recently debated this point with John Angus and colleagues in Science [V. Chakrapani et al., Science 318, 1424; 2007].

From the perspective of water in biology, Andrei suggests the key point is that the highly ordered (indeed, essentially crystalline) water nanofilms he identifies on the (hydrophobic) diamond surface offer “a unique platform for the systematic investigation of nanoscopic water layers.” In a forthcoming paper for Crystal Growth and Design, he and his colleagues Dan Zhu and Hans Fecht argue that these layers might even provide a platform for the origin of life, as I understand it by potentially templating the evolution of organic monolayers. Apparently Albert Szent-Györgyi suggested something similar in the 1970s, proposing such a role for crystalline interfacial water layers. Diamonds can be extremely ancient, and also extraterrestrial. All this is very intriguing, although as someone now programmed to approach with scepticism the notion of enhanced ordering of water at hydrophobic surfaces I think I would like to see some more direct evidence that the water molecules on diamond are indeed truly ordered, especially if the claim is that this extends beyond a monolayer. But I think they’re working on that.

Heme catalases convert hydrogen peroxide to water and oxygen. One type of such enzyme, so-called Clade 3 of the most abundant (monofunctional) class, contains a tightly bound NADPH molecule which seems to protect one of the intermediates of the ferryloxo group against deactivation to a catalytically inactive form. Reiner Sustmann at Duisburg-Essen and colleagues propose in a new paper (W. Sicking et al., JACS 130, 7345-7356; 2008 – paper here) that a bound water molecule plays a critical part in this process, both by supplying a hydroxyl group that binds temporarily to the porphyrin group and then assists the fast two-electron reduction of the intermediate ferryloxo species by NADPH via a series of proton shifts, to restore the catalase resting state and avoid diversion of the reaction towards the deactivated state. A nice example of the multiple, sophisticated roles that bound water can play in active sites.

Lei Zhou and Steven Siegelbaum at Columbia University present a new coarse-grained approach for conducting normal-mode analysis of the dynamics of proteins, which has a lower computational cost than trying to extract the dynamics from a full MD simulation with explicit water [Biophys. J. 94, 3461; 2008 – paper here]. They say that this method is more accurate than are existing coarse-grained NMA techniques, and gives good agreement with experimental results from quasieleastic neutron and light scattering.

In my last blog entry I referred to recent work on the excited-state dynamics of the green fluorescent protein. Dan Huppert and colleagues at Tel Aviv University have looked at essentially the same aspect of the problem: the role of the proton-transfer process [R. Gepshtein et al., Langmuir 112, 7203; 2008 – paper here]. They say that the non-exponential dynamics seem to stem from the distance-dependence of the proton transfer between the chromophore and a bound water molecule that acts as the acceptor. This distance has a relatively large spread of about 0.2 angstroms in GFP.

Finally, thanks to everyone who helped make my Chem. Rev. article a most-accessed paper for the period Jan-Mar 2008.

A mixed bag

Michael Fayer and colleagues at Stanford have looked at how high salt concentrations and nanoconfinement alter orientational relaxation of water’s hydrogen-bonded network using ultrafast IR spectroscopy [S. Park et al., J. Phys. Chem. B 112, 5279-5290; 2008 – paper here.] They find that structural rearrangements of the network are slowed in 6M NaBr, but only moderately – by a factor around 3. The effects of confinement in reverse micelles can be more pronounced, being up to 20 times slower when the ‘nanopools’ of enclosed water are just 1.7 nm across. Moreover, the relaxation then becomes non-exponential. The effect seems to be due more to the effects of confinement per se than to interactions with the charged lipid head groups.

Jim Hynes and Damien Laage have a paper [J. Phys. Chem. B 10.1021/jp802033r] reporting an improved method for determining water residence times in hydration shells in MD simulations, which works with anything from ions to proteins. The key, it seems, is a better handling of the ‘tolerance time’, which relates to frustrated attempts of a water molecule to escape from the first hydration shell.

The spectrum of the green fluorescent protein of the Pacific jellyfish Aequorea Victoria, widely used in molecular biology as a marker, has several absorption bands that are interpreted as resulting from protonation and ionization of certain residues. The excited-state dynamics are thought to involve a proton relay involving three protons that can shuttle along a chain involving a bound water molecule. Ricard Gelabert of the Universitat Autònoma de Barcelona and colleagues have studied this process using a nuclear quantum dynamical simulation, and they find that proton transfer can be extremely fast in this system, initially happening in a matter of femtoseconds (but slowing down in the final stages). Moreover, the three protons seem to travel synchronously along the relay. The transfer induces a conformational change that breaks the relay, and thus is irreversible. The paper [O. Vendrell et al., J. Phys. Chem. B 112, 5500-5511; 2008] is here.

Nikolai Smolin and Valerie Daggett in Seattle have studied the mechanism of a so-called type III antifreeze protein from polar pout (Macrozoarces americanus) using simulations (J. Phys. Chem. B 112, 6193-6202; 2008 – paper here). They’re trying to figure out which of the various possible mechanisms for AFPs seems to apply here, and find that hydration waters on the protein’s ice-binding surface are more tetrahedral and ice-like than those elsewhere in the hydration sphere, suggesting that there is a good epitaxial match that promotes the binding of the protein to incipient ice crystals, preventing their further growth. I’d be interested to know if/how one might rule out the possibility that the protein could in fact provide a site for ice nucleation this way, preventing the growth of large crystals via a proliferation of small ones.

Sinan Keten and Markus Buehler at MIT have an interesting paper in Phys. Rev. Lett. (100, 198301; paper here) on the strength of protein folds secured purely by hydrogen-bonding. They use concepts from conventional fracture mechanics to look at the rupture of H-bonded beta-sheet-like folds, which enables them to conclude that protein domains stabilized this way can’t have rupture forces greater than about 200 pN.

A couple of papers in Langmuir look at the nature of the water-solid interface. Bill Ducker and colleagues have studied the formation of nanobubbles at hydrophobic surfaces, using total-internal-reflection IR spectroscopy to confirm that there are genuine gas-phase molecules present in both air and CO2 bubbles, some as small as just a few nm across to judge from the AFM images also presented (X. H. Zhang et al., Langmuir 24, 4756-4764; 2008 – paper here). The pressures are estimated at around 1-1.7 atm, but while the air bubbles can be stable for days, CO2 bubbles persist for only an hour or two. So while these nanobubbles are not ubiquitous on hydrophobic surfaces, they do form quite routinely.

And Sergio Acuna and Pedro Toledo in Chile have measured short-range forces between glass surfaces in water, using the AFM (Langmuir 24, 4881-4887; 2008 – paper here here). They find a repulsion at short distances (an intervening water film of 3-4 molecular layers) that does not depend on pH or on ion concentration or size. They say that the mechanism of silica hairs, proposed by Israelachvili and Wennerström (Nature 379, 219-225; 1996), can’t explain their data, and that the oscillatory forces they see are due to sequential squeezing out of water layers. I don’t fully understand what the authors mean by attributing this to the ‘creation of a hydrogen-bonding network at the surface level’ – whether this is different from the bulk, say, and why one need invoke hydrogen bonding at all as opposed simply to the kinds of steric packing effects that create oscillatory solvation forces in any solvent.

The paper on water dynamics in cells by Marion Jasnin, Joe Zaccai and colleagues that I mentioned earlier is now published in EMBO Reports, and is available here.

To those who’ve sent me material: I firmly intend to comment on it soon!