[This is a slightly more considered summary of recent work on cryoprotectants, which appears as my Crucible column in the May issue of Chemistry World. The links to the papers discussed can be found in the previous blog entry below.]
When the going gets tough, the tough get sweet. There are many physiological responses to cold conditions, from goose pimples (useless for humans, handier for hairier beasts) to the famous antifreeze proteins of fish. But one of the common strategies for insects is to fill their cells with sugar. It’s still something of a mystery why this helps.
Cold poses diverse threats to life. Ice crystals in the body can simply rupture cell walls, which is why frozen strawberries thaw to a mush. And below about –20 degC protein molecules themselves start to unravel, a process called cold denaturation. That’s not well understood yet either, although a recent paper[1] suggests it involves weakening of the force between hydrophobic (water-repelling) parts of proteins that normally binds the folded form in place.
Sugars such as fructose and trehalose, as well as polyols such as glycerol and ethylene glycol, are manufactured seasonally by insects as cryoprotectants, just as we put antifreeze in our car radiators as winter draws near. Over winter, up to a fifth of the mass of some insects may consist of these substances. One consequence of cell fluid rich in sugar is simple depression of water’s freezing point. But that won’t get you very far into a bitter winter – typically, the depression will be only a few degrees, whereas the Arctic willow gall, flooded with glycerol, will survive temperatures of –66 degC. It’s thought that the cryoprotectants are doing something else here too.
Surviving the cold isn’t always about not getting frozen; sometimes there’s no avoiding it, and cryoprotectants then seem to act as freeze-tolerance rather than freeze-avoidance agents. It’s not only insects that do this: some frogs can survive being frozen solid if they fill their cells with glucose. The sugars and polyols seem to interact with cell water to protect delicate proteins and membranes – but no one is sure how.
Minoru Sakurai of the Tokyo Institute of Technology and his coworkers have shed some light on this through studies of the African midge Polypedilum vanderplanki[2]. They’ve studied not freezing as such, but an environmental stress more common in Africa which has similar consequences: dehydration. Dried larvae of the midge can enter a state called anhydrobiosis, in which they show no metabolic activity but can recover viability when water becomes available. They do this by generating trehalose.
There have been two suggestions for the protective mechanism: either the water is substituted by the sugar, or the sugar promotes the formation of a glassy cell matrix rather than ice crystals. The Japanese team thinks that in fact both are true. They find that the sugar forms hydrogen bonds with the lipids in cell membranes, replacing a shell of hydration water and preventing the membranes from becoming rigid. But the larvae also undergo a distinct glass transition as they are slowly dried. The glass is not pure trehalose, but is peppered with other components, such as proteins, that might help to disrupt crystallization.
How, though, does a shell of sugar or polyol protect a protein when water cannot? It seems that cryoprotectants can stabilize proteins against unfolding, but whether this comes from direct protein-sugar interactions or some kind of sugar-induced modification of water structure isn’t clear. Martina Havenith at the Ruhr University of Bochum and her colleagues recently reported signs that the latter might play a role[3]. Using terahertz spectroscopy, they found that the dynamics of water molecules are disturbed a remarkably long distance away from dissolved sugars – up to about 5-7 Å for trehalose and lactose. These perturbations are stronger and longer-ranged for disaccharides than for the monosaccharide glucose, which would support the notion that cryoprotection (which disacchardides do better) is tied up with the sugar’s ability to slow down the water motions and promote a pseudo-glassy state.
Findings by Giovanni Strambini and coworkers at the Consiglio Nazionale delle Ricerche in Pisa, Italy, could be seen to lend support to this idea. The Italian team have asked how cryoprotectants do their job if ice actually begins to form. They used fluorescence spectroscopy to study the stabilization of a protein called azurin by sugars and polyols (sucrose, trehalose, sorbitol, glycerol) in ice-water mixtures[4]. It seems none of these molecules offers strong protection against ice formation, although trehalose ‘tries hardest’: as ice appears, the protein is increasingly prone to unfold. So the cryoprotectants don’t make the native protein significantly more thermodynamically stable. Instead, the researchers think that they somehow cajole the protein to stay folded in the liquid until the whole system becomes a sluggish glass and unfolding is then simply too slow – a kinetic rather than thermodynamic effect.
So there is an emerging picture, albeit a complex one. The cryoprotectants could have a dual role. First they remodel biomolecular hydration shells, retarding water and maybe suppressing the loss of crucial protein-folding forces. Then they eventually promote the formation of a glassy matrix rather than an icy one, arresting the biomolecular structures in recoverable suspended animation. That’s clever work for a spoonful of sugar.
References
1. C. L. Dias et al., Phys. Rev. Lett. 100, 118101 (2008).
2. M. Sakurai et al., Proc. Natl Acad. Sci. USA 105, 5093-5098 (2008).
3. M. Heyden et al., J. Am. Chem. Soc. doi:10.1021/ja0781083.
4. G. B. Strambini et al., J. Phys. Chem. B 112, 4372-4380 (2008).
Friday, May 2, 2008
Tuesday, April 8, 2008
Surviving the winter
How do some organisms survive dehydration? In the state called anhydrobiosis, such organisms exhibit a kind of suspended animation, showing no apparent metabolic activity but reviving when rehydrated. Two explanations for this behaviour have been proposed: replacement of water by another medium, such as sugars, and the formation of a glassy matrix (vitrification). Takashi Okuda of the National Institute of Agrobiological Sciences in Tsukuba, Japan, and his colleagues have reported evidence that, at least for the case of the African midge Polypedilum vanderplanki, both these hypotheses seem to apply [M. Sakurai et al., PNAS 105, 5093-5098; 2008 – paper here]. They find that anhydrobiotic larvae of this insect are in a glassy state in which much of the water is replaced with trehalose. They think that the glassy matrix is a mixture of trehalose with other components, such as highly hydrophilic proteins. The big question is surely how the organisms get into and out of the glassy state: if moisture uptake or high temperature turns the sugar glass rubbery, the larvae lose their viability.
The production of trehalose and other compatible solutes is of course one of the common mechanisms of freeze-tolerance. Cold conditions threaten organisms not just because of the physical disruption caused by ice crystal formation, but because proteins may denature below about minus 20 Centigrade. The mechanism of cold denaturation has been much debated. Cristiano Dias of the University of Montreal and colleagues propose [C. L. Dias et al., Phys. Rev. Lett. 100, 118101; 2008 – paper here] that it shares characteristics with pressure-induced denaturation, which Gerhard Hummer and his coworkers have previously attributed to the destabilization of hydrophobic contacts in favour of solvent-separated ones [G. Hummer et al., PNAS 95, 1552; 1998]. In other words, the idea is that both effects are all about the temperature- and pressure-dependence of the hydrophobic interaction. Dias and colleagues support this conclusion with 2D molecular-dynamics simulations, which suggest that at low temperatures water molecules in a protein’s hydration shell hydrogen-bond more strongly than those in the bulk.
It’s a bit of a month for studies of freeze/dehydration tolerance. Martina Havenith at Bochum and colleagues have used terahertz spectroscopy to show surprisingly long-ranged correlations between sub-picosecond dynamics in water close to and further from dissolved cabohydrates (trehalose, lactose, glucose) [M. Heyden et al., JACS doi:10.1021/ja0781083– paper here]. That is, the effects persist over about 5-7 Å, suggesting that this is in effect the width of the hydration shell for these sugars. The perturbations are stronger for the disaccharides than the monosaccharide (here the influence extends only to about 3-4 Å), which the authors connect with the stronger cryoprotection activity of the former – that is, it would support the notion that this protection is conferred by a disruption (retardation) of the solvent dynamics.
And Giovanni Strambini and coworkers at the Consiglio Nazionale delle Ricerche in Pisa, Italy, have used fluorescence spectroscopy to study the stabilization of the azurin protein by sugars and polyols in ice [G. B. Strambini et al., J. Phys. Chem. B 112, 4372-4380; 2008 – paper here]. One question they have set out to address is: to what extent are the cryoprotectants defending against low temperature per se, and to what extent against ice formation? In fact, none of the molecules (sucrose, trehalose, sorbitol, glycerol) seems to fully protect against ice formation, although trehalose ‘tries hardest’. It seems that the role of the cryoprotectants is not to increase the thermodynamic stability of the native fold per se, but to help hold it together specifically in the liquid phase. Curiously, some of them do this less effectively at minus 15 C than at lower temperatures – which seems to be because once it gets cold enough, denaturation becomes kinetically rather than thermodynamically controlled: unfolding is simply too slow. There is an interesting story building here.
More on low-temperature protein dynamics comes from Jeremy Smith and his coworkers Vandana Kurkal-Siebert and Ritesh Agarwal at Heidelberg [Phys. Rev. Lett. 100, 138102; 2008 – paper here]. They have used MD simulations to look at interprotein dynamical interactions in hydrated crystals of carboxymyoglobin, a kind of proxy for protein-protein interactions more generally. In fully hydrated crystals there is a dynamical transition at around 240 K due to intermolecular fluctuations, whereas no such behaviour is seen for low hydration. This is reminiscent of the 220 K intramolecular dynamical transition seen in proteins, which resembles (but may not in fact be – see below) a glass transition. If I’ve understood this properly, the idea is that the (diffusive) intermolecular motions in the proteins must therefore be mediated (activated) by those in the hydration shells.
The dynamics of proteins in this pseudo-glassy state below about 220 K do indeed seem to get very closely coupled – perhaps ‘slaved’ – to the similar non-Arrhenius dynamics of the solvent. Now Martin Weik and a host of others have confirmed this coupling using neutron scattering [K. Wood et al., JACS 10.1021/ja710526r – paper here]. They find that below the transition temperature, the protein (here maltose binding protein) is structurally arrested in a glassy solvent cage, while at around 220 K ‘fast’ protein motions are reawakened at precisely the same time as hydration water starts to show diffusive translational motion. In a nutshell, as the authors put it, “the protein dynamical transition is correlated with relaxation of the protein H-bond network, which, in turn, is associated with the onset of water translational diffusion.”
Sow-Hsin Chen at MIT and his coworkers have previously related this dynamical transition to that in pure water predicted on the basis of a liquid-liquid transition at high pressure, which creates a kind of ‘ghost’ of the transition called the Widom line at lower pressures (see S.-H. Chen et al., PNAS 103, 9012; 2006). They now report further evidence, from SANS studies of water in mesoporous silica (MCM-41), of a change in the structure and dynamics of water at around 235 K due to crossing of the Widom line [D. Liu et al., J. Phys. Chem. B 112, 4309-4312; 2008 – paper here] .
Finally (for now), Roland Netz and colleagues at the Technical University of Munich have attempted to simplify studies of the hydrophobic attraction, which has typically involved mesoscopic surfaces on which many length scales can be important, by investigating the force required to peel a single, mildly hydrophobic peptide from a diamond surface [D. Horinek et al., PNAS 105, 2842-2847; 2008 – paper here]. They compare their experimental results using atomic force spectroscopy with simulation, to try to quantify the relative contributions of dispersion forces between the two surfaces and ‘water structure’ effects. They find that all the individual pairwise interactions between the peptide, the surface and the solvent are larger than the total desorption energy, but opposite in sign while being of similar magnitude, so that they almost cancel out.
The production of trehalose and other compatible solutes is of course one of the common mechanisms of freeze-tolerance. Cold conditions threaten organisms not just because of the physical disruption caused by ice crystal formation, but because proteins may denature below about minus 20 Centigrade. The mechanism of cold denaturation has been much debated. Cristiano Dias of the University of Montreal and colleagues propose [C. L. Dias et al., Phys. Rev. Lett. 100, 118101; 2008 – paper here] that it shares characteristics with pressure-induced denaturation, which Gerhard Hummer and his coworkers have previously attributed to the destabilization of hydrophobic contacts in favour of solvent-separated ones [G. Hummer et al., PNAS 95, 1552; 1998]. In other words, the idea is that both effects are all about the temperature- and pressure-dependence of the hydrophobic interaction. Dias and colleagues support this conclusion with 2D molecular-dynamics simulations, which suggest that at low temperatures water molecules in a protein’s hydration shell hydrogen-bond more strongly than those in the bulk.
It’s a bit of a month for studies of freeze/dehydration tolerance. Martina Havenith at Bochum and colleagues have used terahertz spectroscopy to show surprisingly long-ranged correlations between sub-picosecond dynamics in water close to and further from dissolved cabohydrates (trehalose, lactose, glucose) [M. Heyden et al., JACS doi:10.1021/ja0781083– paper here]. That is, the effects persist over about 5-7 Å, suggesting that this is in effect the width of the hydration shell for these sugars. The perturbations are stronger for the disaccharides than the monosaccharide (here the influence extends only to about 3-4 Å), which the authors connect with the stronger cryoprotection activity of the former – that is, it would support the notion that this protection is conferred by a disruption (retardation) of the solvent dynamics.
And Giovanni Strambini and coworkers at the Consiglio Nazionale delle Ricerche in Pisa, Italy, have used fluorescence spectroscopy to study the stabilization of the azurin protein by sugars and polyols in ice [G. B. Strambini et al., J. Phys. Chem. B 112, 4372-4380; 2008 – paper here]. One question they have set out to address is: to what extent are the cryoprotectants defending against low temperature per se, and to what extent against ice formation? In fact, none of the molecules (sucrose, trehalose, sorbitol, glycerol) seems to fully protect against ice formation, although trehalose ‘tries hardest’. It seems that the role of the cryoprotectants is not to increase the thermodynamic stability of the native fold per se, but to help hold it together specifically in the liquid phase. Curiously, some of them do this less effectively at minus 15 C than at lower temperatures – which seems to be because once it gets cold enough, denaturation becomes kinetically rather than thermodynamically controlled: unfolding is simply too slow. There is an interesting story building here.
More on low-temperature protein dynamics comes from Jeremy Smith and his coworkers Vandana Kurkal-Siebert and Ritesh Agarwal at Heidelberg [Phys. Rev. Lett. 100, 138102; 2008 – paper here]. They have used MD simulations to look at interprotein dynamical interactions in hydrated crystals of carboxymyoglobin, a kind of proxy for protein-protein interactions more generally. In fully hydrated crystals there is a dynamical transition at around 240 K due to intermolecular fluctuations, whereas no such behaviour is seen for low hydration. This is reminiscent of the 220 K intramolecular dynamical transition seen in proteins, which resembles (but may not in fact be – see below) a glass transition. If I’ve understood this properly, the idea is that the (diffusive) intermolecular motions in the proteins must therefore be mediated (activated) by those in the hydration shells.
The dynamics of proteins in this pseudo-glassy state below about 220 K do indeed seem to get very closely coupled – perhaps ‘slaved’ – to the similar non-Arrhenius dynamics of the solvent. Now Martin Weik and a host of others have confirmed this coupling using neutron scattering [K. Wood et al., JACS 10.1021/ja710526r – paper here]. They find that below the transition temperature, the protein (here maltose binding protein) is structurally arrested in a glassy solvent cage, while at around 220 K ‘fast’ protein motions are reawakened at precisely the same time as hydration water starts to show diffusive translational motion. In a nutshell, as the authors put it, “the protein dynamical transition is correlated with relaxation of the protein H-bond network, which, in turn, is associated with the onset of water translational diffusion.”
Sow-Hsin Chen at MIT and his coworkers have previously related this dynamical transition to that in pure water predicted on the basis of a liquid-liquid transition at high pressure, which creates a kind of ‘ghost’ of the transition called the Widom line at lower pressures (see S.-H. Chen et al., PNAS 103, 9012; 2006). They now report further evidence, from SANS studies of water in mesoporous silica (MCM-41), of a change in the structure and dynamics of water at around 235 K due to crossing of the Widom line [D. Liu et al., J. Phys. Chem. B 112, 4309-4312; 2008 – paper here] .
Finally (for now), Roland Netz and colleagues at the Technical University of Munich have attempted to simplify studies of the hydrophobic attraction, which has typically involved mesoscopic surfaces on which many length scales can be important, by investigating the force required to peel a single, mildly hydrophobic peptide from a diamond surface [D. Horinek et al., PNAS 105, 2842-2847; 2008 – paper here]. They compare their experimental results using atomic force spectroscopy with simulation, to try to quantify the relative contributions of dispersion forces between the two surfaces and ‘water structure’ effects. They find that all the individual pairwise interactions between the peptide, the surface and the solvent are larger than the total desorption energy, but opposite in sign while being of similar magnitude, so that they almost cancel out.
Wednesday, March 26, 2008
Chemistry vs geometry
Pablo Debenedetti and colleagues have carried out precisely the kind of study that is needed to tease apart the various factors that might be at play in hydrophobic association of proteins (N. Giovambattista et al., PNAS 105, 2274-2279; 2008 – paper here). One can anticipate that the potential for effects such as abrupt drying transitions as the two surfaces approach is affected both by surface chemistry – by the distribution of hydrophilic and hydrophobic groups – and by geometry. Certainly, both have been implicated as playing a role in how real proteins behave, as for example in the Berne group’s study of protein associations for BphC and melittin (Liu et al., Nature 437, 159-162; 2005; Zhou et al., Science 305, 1605-1609; 2004). Melittin monomers enclose a tubelike space, for example, whereas BphC is slablike. Moreover, melittin, like many proteins, has a rough surface with concavities. To decouple the effects, Pablo and colleagues have simulated the association of a mutated melittin dimer in which the distribution of hydrophobic and hydrophilic groups is retained but the surface is artificially flattened. The results suggest that the flattened melittin behaves as an intermediate case between ideal, flat hydrophobic and hydrophilic surfaces, and that the drying seen in the case of ‘real’ melittin happens only at very small separations (about one intervening water layer) for the flattened case, being localized to a central region where an apolar residue resides. It can be suppressed by replacing that residue. In other words, drying seen for ideal hydrophobic plates is probably stronger than it is for real proteins, where it is likely to be highly sensitive to small variations in surface chemistry.
Michael Geisler and colleagues at the Technical University of Munich have looked at Hofmeister effects in the adhesion of spider silk proteins to a solid surface, using single-molecule AFM force spectroscopy (Langmuir 24, 1350-1355; 2008 – paper here). They find that the desorption forces follow the Hofmeister series, but can’t yet develop a clear interpretation of what is going on. The hydrophobicity of the silk protein also plays a part: ions that stabilize adhesion do so less when the protein is less hydrophobic, ‘indicating that hydrophobic and Hofmeister effects are closely related’ – but how?
Dusan Bratko and Alenka Luzar have attempted to unravel the much vexed question of how dissolved gases affect the hydrophobic interaction (Langmuir 24, 1247-1253; 2008 – paper here). They have used simulations to look at how various gases influence water structure close to a hydrophobic surface, and solvation forces between two such surfaces. They say that although there does seem to be accumulation of dissolved gas at the interface, it doesn’t have a big effect either on putative water depletion or on solvation forces – something that several experiments seem to bear out. One of the nice aspects of this work is that it enables the authors to make a link between capillary evaporation of pure water induced by hydrophobic confinement and evaporation nucleated by an excess of dissolved gas at the interface – two things that are sometimes not so clearly distinguished. But the simulations can’t follow the possible formation of nanobubbles and the effect this might have on the hydrophobic interaction.
Finally, I have good reason to think that my recent Essay in Nature on water (here) might be seen by some as an endorsement of the ‘new view’ of water structure championed by Anders Nilsson and Lars Pettersson. It’s not, as I think is clear if you read carefully. I merely point out that, first, it is remarkable that such fundamental disagreements about water are still occurring (I know, of course, that Anders and Lars’ idea has been strongly criticized), and secondly, that the implications are rather more far-reaching than might be naively supposed. I must apologize, incidentally, for giving the impression that the experimental work on which their new model is based was done by Lars at Stockholm, rather than by Anders at Stanford.
Michael Geisler and colleagues at the Technical University of Munich have looked at Hofmeister effects in the adhesion of spider silk proteins to a solid surface, using single-molecule AFM force spectroscopy (Langmuir 24, 1350-1355; 2008 – paper here). They find that the desorption forces follow the Hofmeister series, but can’t yet develop a clear interpretation of what is going on. The hydrophobicity of the silk protein also plays a part: ions that stabilize adhesion do so less when the protein is less hydrophobic, ‘indicating that hydrophobic and Hofmeister effects are closely related’ – but how?
Dusan Bratko and Alenka Luzar have attempted to unravel the much vexed question of how dissolved gases affect the hydrophobic interaction (Langmuir 24, 1247-1253; 2008 – paper here). They have used simulations to look at how various gases influence water structure close to a hydrophobic surface, and solvation forces between two such surfaces. They say that although there does seem to be accumulation of dissolved gas at the interface, it doesn’t have a big effect either on putative water depletion or on solvation forces – something that several experiments seem to bear out. One of the nice aspects of this work is that it enables the authors to make a link between capillary evaporation of pure water induced by hydrophobic confinement and evaporation nucleated by an excess of dissolved gas at the interface – two things that are sometimes not so clearly distinguished. But the simulations can’t follow the possible formation of nanobubbles and the effect this might have on the hydrophobic interaction.
Finally, I have good reason to think that my recent Essay in Nature on water (here) might be seen by some as an endorsement of the ‘new view’ of water structure championed by Anders Nilsson and Lars Pettersson. It’s not, as I think is clear if you read carefully. I merely point out that, first, it is remarkable that such fundamental disagreements about water are still occurring (I know, of course, that Anders and Lars’ idea has been strongly criticized), and secondly, that the implications are rather more far-reaching than might be naively supposed. I must apologize, incidentally, for giving the impression that the experimental work on which their new model is based was done by Lars at Stockholm, rather than by Anders at Stanford.
Tuesday, March 11, 2008
Antifreeze: what the sugar does
First, an historical note: I recently discovered that this very nice paper by Charles Tanford on the history of the hydrophobic effect is available online. Much of this stuff appears in his books The Hydrophobic Effect (Wiley, 1980) and Nature’s Robots (OUP, 2001), but it’s a very nice summary of it.
Joe Zaccai has sent me a preprint of a paper just accepted by EMBO Reports that uses neutron scattering to look at water dynamics in vivo in E. coli. It shows that these dynamics are ‘normal’ and bulk-like, contrary to suggestions that water is ‘tamed’ in the cytoplasm. Bertil Halle and his coworkers have a paper in press with PNAS that reports precisely the same conclusion based on NMR data. So together, these papers ought to bury one more water myth.
There’s an interesting study here (JACS 130, 2928-2929; 2008) by Robert Ben and colleagues at Ottawa of the effect of sugar hydration on the antifreeze behaviour of glycoproteins. By substituting various sugars on antifreeze glycoprotein analogues, they find that the sugar conformation and thus hydration is important for inhibition of ice recrystallization. Here’s the punchline: “our data indicate that the compatibility of a hexose with the three-dimensional hydrogen-bonded network of water is inversely proportional to recrystallization-inhibition activity” – a finding they associate with the consequent free-energy change of transferring a water molecule to the ice lattice.
Also in JACS (130, 3120-3126; paper here), Greg Voth and his coworkers Feng Wang and Sergei Izvekov report ab initio MD simulations showing that hydronium ions form unusual cation pairs in concentrated aqueous HCl, stabilized by delocalization of the excess charge of the hydrated proton. This is consistent with Greg’s earlier work showing that hydronium seems to display amphiphilic behaviour – one can regard this as a kind of amphiphilic clustering.
Water does interesting stuff around benzene, which is hydrophobic around the edges but can form hydrogen bonds via the pi orbitals over the ring faces. So how does this translate to C60? Dahlia Weiss, Tanya Raschke and Michael Levitt have addressed that question using MD simulations in a paper here (J. Phys. Chem. B 112, 2981-2990; 2008). They say that the waters in the first hydration shell become more oriented, and have an increased number of hydrogen-bonding contacts, but that hydrogen bonding is disrupted between the first and second hydration shells. In general, the hydration shell is dense and ‘well-structured’ – I’d guess consistent, at a glance, with the kinds of orientational ordering described by Jan Engberts and W. Blokzijl in their 1993 article on hydrophobicity (Angew. Chem. Int. Ed. 32, 1545-1579), as opposed to the old notion of a hydrophobic ‘iceberg’. In this regard, the authors say that “C60 behaves as a large hydrophobic solute.”
Joe Zaccai has sent me a preprint of a paper just accepted by EMBO Reports that uses neutron scattering to look at water dynamics in vivo in E. coli. It shows that these dynamics are ‘normal’ and bulk-like, contrary to suggestions that water is ‘tamed’ in the cytoplasm. Bertil Halle and his coworkers have a paper in press with PNAS that reports precisely the same conclusion based on NMR data. So together, these papers ought to bury one more water myth.
There’s an interesting study here (JACS 130, 2928-2929; 2008) by Robert Ben and colleagues at Ottawa of the effect of sugar hydration on the antifreeze behaviour of glycoproteins. By substituting various sugars on antifreeze glycoprotein analogues, they find that the sugar conformation and thus hydration is important for inhibition of ice recrystallization. Here’s the punchline: “our data indicate that the compatibility of a hexose with the three-dimensional hydrogen-bonded network of water is inversely proportional to recrystallization-inhibition activity” – a finding they associate with the consequent free-energy change of transferring a water molecule to the ice lattice.
Also in JACS (130, 3120-3126; paper here), Greg Voth and his coworkers Feng Wang and Sergei Izvekov report ab initio MD simulations showing that hydronium ions form unusual cation pairs in concentrated aqueous HCl, stabilized by delocalization of the excess charge of the hydrated proton. This is consistent with Greg’s earlier work showing that hydronium seems to display amphiphilic behaviour – one can regard this as a kind of amphiphilic clustering.
Water does interesting stuff around benzene, which is hydrophobic around the edges but can form hydrogen bonds via the pi orbitals over the ring faces. So how does this translate to C60? Dahlia Weiss, Tanya Raschke and Michael Levitt have addressed that question using MD simulations in a paper here (J. Phys. Chem. B 112, 2981-2990; 2008). They say that the waters in the first hydration shell become more oriented, and have an increased number of hydrogen-bonding contacts, but that hydrogen bonding is disrupted between the first and second hydration shells. In general, the hydration shell is dense and ‘well-structured’ – I’d guess consistent, at a glance, with the kinds of orientational ordering described by Jan Engberts and W. Blokzijl in their 1993 article on hydrophobicity (Angew. Chem. Int. Ed. 32, 1545-1579), as opposed to the old notion of a hydrophobic ‘iceberg’. In this regard, the authors say that “C60 behaves as a large hydrophobic solute.”
Tuesday, March 4, 2008
Solvent not included
I talked a little bit in my review article about the difficulty of understanding and/or predicting the energetics of water expulsion from the active site of a protein when it binds its ligand, and the potential value of being able to do so for drug design. Richard Friesner, Bruce Berne and their colleagues have now reported a computational model which they say allows them to make this calculation in an efficient manner (JACS 130, 2817-2831; 2008 – paper here). They test it out on ligand binding in factor Xa, a potential anti-thrombosis drug target. They imply that this approach, considering a molecularly resolved rather than a continuum solvent, is needed for accurate prediction of the significant contributions that such displacements can make to the binding energies.
There’s more on this issue by Anthony Davis and colleagues at Bristol (E. Klein et al., Angew. Chem. Int. Ed. 10.1002/anie.200704733; paper here), who look at the role of displaced water in binding of carbohydrates by synthetic receptors (which they argue to be good analogues of carbohydrate-binding proteins). They say that hydrophobic interactions – which I think means here the expulsion of water from hydrophobic-hydrophobic contacts – play a significant role in binding.
Also somewhat related is a paper by Ken Raymond and colleagues at Berkeley, who have probed the influence of solvation on supramolecular encapsulation processes (Leung et al., JACS 130, 2798-2805; 2008 – paper here). They look at the subtle compensation effects between enthalpic and entropic contributions to encapsulation free energy: in water, desolvation releases water molecules to form more hydrogen bonds in the bulk, which is enthalpically favourable but entropically not. They conclude that the primary driving force of encapsulation, in water and other polar protic solvents, is the rearrangement of the hydrogen-bonding network in the solvent.
A recent paper on segregation of hydronium ions at air-water (and by extension, hydrophobic) surfaces, claiming that these have elevated pH (Buch et al., PNAS 104, 7342; 2007) stirred up some controversy. Some others claim that in fact such water surfaces are enriched with hydroxide, not hydronium. Konstantin Kudin and Roberto Car have now looked at both cases, using ab initio molecular dynamics simulations (JACS doi:10.1021/ja077205t; paper here). They say that both hydroxide and hydronium act as amphiphiles at these interfaces, with one end even more hydrophilic than water and the other essentially hydrophobic. The effect is larger for hydroxide, which implies that these ions accumulate more readily at the surface, giving it a negative charge. That’s indeed what seems to be observed in practice, as James Beattie pointed out to me when I wrote about the Buch et al. paper. But the results also seem consistent with Greg Voth’s predictions that hydronium acts as an amphiphile (e.g M. K. Petersen et al., J. Phys. Chem. B 108, 14804; 2004).
It’s very heartening to see in such a prominent place (Science 319,1197-1198; 2008) Douglas Tobias and John Hemminger’s head-on challenge to the notion of generalized structure-making and structure-breaking of water as an explanation for Hofmeister (specific-ion) effects. Tobias and Hemminger’s piece is a perspective on two recent papers mentioned earlier on this blog (Smith et al., JACS 129, 13847; 2007 and Mancinelli et al., J.Phys. Chem. B 109, 13570; 2007). I won’t outline those papers again, but simply point out that they both, from different perspectives, highlighted shortcomings of the traditional picture. T&H point out that recent work on specific ion absorption or depletion at surfaces by Jungwirth, Saykally, Pegram and Record, Berne and others are beginning to point to a rather more complicated picture of electrolyte effects that has nothingto do with modifications of the bulk structure of water.
Julio Fernandez and colleagues (first author Lorna Dougan at Columbia) argue here (PNAS 105, 3185-3190; 2008) that the mechanical functions of proteins, which involve conformational changes, are highly sensitive to the solvent because of solvent bridges between parts of the polypeptide chain. This is consistent with earlier work by Jose Onuchic and collaborators on protein folding (e.g. PNAS 99, 685; 2002). Dougan et al. use single-molecule force spectroscopy on a repeating-sequence domain of titin, a component of muscle tissue, to study how stretching it out changes when the solvent is switched to deuterium oxide or glycerol. The results are consistent with simulations in which the solvent molecules bridge adjacent beta-strands in the unfolding transition state. For water, several bridges of one molecule each seem to be involved; for glycerol, with a longer hydrogen-bonding ‘reach’, this transition state corresponds to a wider strand separation. Here the unfolding is an intrinsic part of the protein’s biological role, but presumably the same considerations would be expected to apply to denaturation of globular proteins too.
Fengshou Zhang at the Beijing Normal University has sent me a preprint of his paper now published in Phys. Rev. Lett. 100, 088104 (2008), in which he and his colleagues report MD simulations of conformational changes in DNA brought about by changes in solvent. Specifically, they consider ‘modified water’ with a tetrahedral structure but with variable dipole moment, ranging from ‘over-polarized’ (relative towater) to under-polarized. In the former case the double-helical B form is maintained but becomes stiffer (smaller fluctuations); as polarity decreases, the A form becomes increasingly favoured. The authors relate this to changes in phosphate screening, which is effected mainly by solvent molecules in more polar solvents and by counterions in less polar ones. I’m interested that Ruth Lynden-Bell is thanked for discussions; Ruth has pioneered this notion of a kind of counterfactual exploration of water’s role in structural biology, as a way of investigating the notion of ‘fine-tuning’ of water in biology (or should it be, of biology in water?).
There’s more good stuff to come, but that’s enough for now. It is very nice to be getting sent these things...
There’s more on this issue by Anthony Davis and colleagues at Bristol (E. Klein et al., Angew. Chem. Int. Ed. 10.1002/anie.200704733; paper here), who look at the role of displaced water in binding of carbohydrates by synthetic receptors (which they argue to be good analogues of carbohydrate-binding proteins). They say that hydrophobic interactions – which I think means here the expulsion of water from hydrophobic-hydrophobic contacts – play a significant role in binding.
Also somewhat related is a paper by Ken Raymond and colleagues at Berkeley, who have probed the influence of solvation on supramolecular encapsulation processes (Leung et al., JACS 130, 2798-2805; 2008 – paper here). They look at the subtle compensation effects between enthalpic and entropic contributions to encapsulation free energy: in water, desolvation releases water molecules to form more hydrogen bonds in the bulk, which is enthalpically favourable but entropically not. They conclude that the primary driving force of encapsulation, in water and other polar protic solvents, is the rearrangement of the hydrogen-bonding network in the solvent.
A recent paper on segregation of hydronium ions at air-water (and by extension, hydrophobic) surfaces, claiming that these have elevated pH (Buch et al., PNAS 104, 7342; 2007) stirred up some controversy. Some others claim that in fact such water surfaces are enriched with hydroxide, not hydronium. Konstantin Kudin and Roberto Car have now looked at both cases, using ab initio molecular dynamics simulations (JACS doi:10.1021/ja077205t; paper here). They say that both hydroxide and hydronium act as amphiphiles at these interfaces, with one end even more hydrophilic than water and the other essentially hydrophobic. The effect is larger for hydroxide, which implies that these ions accumulate more readily at the surface, giving it a negative charge. That’s indeed what seems to be observed in practice, as James Beattie pointed out to me when I wrote about the Buch et al. paper. But the results also seem consistent with Greg Voth’s predictions that hydronium acts as an amphiphile (e.g M. K. Petersen et al., J. Phys. Chem. B 108, 14804; 2004).
It’s very heartening to see in such a prominent place (Science 319,1197-1198; 2008) Douglas Tobias and John Hemminger’s head-on challenge to the notion of generalized structure-making and structure-breaking of water as an explanation for Hofmeister (specific-ion) effects. Tobias and Hemminger’s piece is a perspective on two recent papers mentioned earlier on this blog (Smith et al., JACS 129, 13847; 2007 and Mancinelli et al., J.Phys. Chem. B 109, 13570; 2007). I won’t outline those papers again, but simply point out that they both, from different perspectives, highlighted shortcomings of the traditional picture. T&H point out that recent work on specific ion absorption or depletion at surfaces by Jungwirth, Saykally, Pegram and Record, Berne and others are beginning to point to a rather more complicated picture of electrolyte effects that has nothingto do with modifications of the bulk structure of water.
Julio Fernandez and colleagues (first author Lorna Dougan at Columbia) argue here (PNAS 105, 3185-3190; 2008) that the mechanical functions of proteins, which involve conformational changes, are highly sensitive to the solvent because of solvent bridges between parts of the polypeptide chain. This is consistent with earlier work by Jose Onuchic and collaborators on protein folding (e.g. PNAS 99, 685; 2002). Dougan et al. use single-molecule force spectroscopy on a repeating-sequence domain of titin, a component of muscle tissue, to study how stretching it out changes when the solvent is switched to deuterium oxide or glycerol. The results are consistent with simulations in which the solvent molecules bridge adjacent beta-strands in the unfolding transition state. For water, several bridges of one molecule each seem to be involved; for glycerol, with a longer hydrogen-bonding ‘reach’, this transition state corresponds to a wider strand separation. Here the unfolding is an intrinsic part of the protein’s biological role, but presumably the same considerations would be expected to apply to denaturation of globular proteins too.
Fengshou Zhang at the Beijing Normal University has sent me a preprint of his paper now published in Phys. Rev. Lett. 100, 088104 (2008), in which he and his colleagues report MD simulations of conformational changes in DNA brought about by changes in solvent. Specifically, they consider ‘modified water’ with a tetrahedral structure but with variable dipole moment, ranging from ‘over-polarized’ (relative towater) to under-polarized. In the former case the double-helical B form is maintained but becomes stiffer (smaller fluctuations); as polarity decreases, the A form becomes increasingly favoured. The authors relate this to changes in phosphate screening, which is effected mainly by solvent molecules in more polar solvents and by counterions in less polar ones. I’m interested that Ruth Lynden-Bell is thanked for discussions; Ruth has pioneered this notion of a kind of counterfactual exploration of water’s role in structural biology, as a way of investigating the notion of ‘fine-tuning’ of water in biology (or should it be, of biology in water?).
There’s more good stuff to come, but that’s enough for now. It is very nice to be getting sent these things...
Thursday, February 7, 2008
Some old, lots new
I seem somehow to have overlooked a couple of highly relevant review articles in my Chem. Rev. paper. One is Ken Dill’s piece on ‘Modeling water, the hydrophobic effect, and ion solvation’:
K. A. Dill, T. M. Truskett, V. Vlachy & B. Hribar-Lee, Annu. Rev. Biophys. Biomol. Struct. 34, 173-199 (2005).
(Get it here.)
The other is Martin Chaplin’s paper ‘Do we underestimate the importance of water in cell biology?’, which, as the title implies, provides a much briefer overview of most of the issues I discuss in my review and carries the same basic message:
M. F. Chaplin, Nature Rev. Mol. Cell Biol. 7, 861-866 (2006).
(Get it here.)
Apologies for these omissions.
Moving on to things new… David Chandler’s comments on the mechanism of dewetting-induced hydrophobic assembly in my last post are expanded on in some detail in a new paper (A. P. Willard & D. Chandler, J. Phys. Chem. B doi:10.1021/jp077186+). They argue that the motions of the hydrophobic solutes are such that the basic cavitation process to form the ‘vapour bridge’ can have zero activation energy.
One of my favourite papers of the moment comes from Martina Havenith at Bochum and colleagues (S. Ebbinghaus et al., PNAS 104, 20749-20752; 2007). They have used terahertz spectroscopy and MD simulations to probe the hydration layer around proteins, in particular to estimate how thick it is. They find that differences in correlated water motions, relative to the bulk, extend to more than 2 nm from the protein surface. It’s a remarkable and important demonstration of the extra ‘reach’ that solvation affords biological macromolecules, and really makes the case for why the hydration layer needs to be considered in some sense a part of the molecule it encompasses, making them fuzzy-edged entities with a sphere of influence that stretches well beyond the apparent surface.
Martina and her colleagues have also looked at how this solvation structure is altered by mutations and by pH (S. Ebbinghaus et al., JACS doi:10.1021/ja0746520; paper here). They find that a single mutation of the five-helix bundle lambda*[6-85], replacing a glutamine side chain with aromatic residues, significantly reduces the reach of the perturbation to the solvation water. This distance is also reduced when the wild-type protein is denatured at pH 2. It will be interesting to know if both are general effects, implying that proteins are somehow optimized to induce maximum restructuring of the solvent.
Bertil Halle has sent me a preprint of a paper just accepted in PNAS, in which he along with Johan Qvist and Monika Davidovic at Lund, and Donald Hamelberg at UCSD, report a wholly water-free large hydrophobic cavity in bovine beta-lactoglobulin. This cavity, called the calyx and acting as a binding site for fatty acids and other nonpolar ligands, has a volume of 315 cubic Å. The authors contrast this with the interior of carbon nanotubes, which is nominally hydrophobic but threaded by water chains. It shows just how amazingly dry nature can keep itself when the need arises.
Bertil also has a new paper) with Erik Persson describing how magnetic relaxation dispersion studies of water molecules buried inside proteins can provide a probe of ns- to ms-timescale protein dynamics (E. Persson & B. Halle, JACS 130, 1774-1787; 2008).
Talking of water in nanotubes, Hideki Tanaka and his colleagues at Okayama University have ised MD simulations to map out the complete phase diagram of water in nanotubes at atmospheric pressure for diameters up to 1.7 nm (D. Takaiwa et al., PNAS 105, 39-43; 2008; paper here). They find at least nine different ice phases, each apparently adapting to the confined space in a way that maximizes the number of hydrogen bonds. They say that the confined liquid water doesn’t show a density maximum above freezing point, and that it shrinks on freezing. Nor is freezing necessarily a first-order transition here. All a rather beautiful picture of how profoundly confinement can alter water’s properties.
There’s a curious paper in Langmuir (A. P. Sommer, A. Caron & H.-J. Fecht, Langmuir 24, 635-636; 2008) claiming that ‘ordered interfacial water’ near hydrophobic and hydrophilic surfaces can be tuned with laser light, and that the light causes an increase in fluidity, presumed (as far as I can make out) to be due to depletion of the ‘ordered’ layer, in the hydrophilic case. I’m left wondering whether there is really any direct evidence for ‘increased ordering’ in these interfacial layers, and what precisely that means here. Something interesting seems to be happening, but I don’t think it’s clear what it is.
Aizhuo Liu et al. in Michigan report what they call ‘bifurcated’ hydrogen bonds in proteins, using isotope substitution studied with NMR (A. Liu et al., JACS doi:10.1021/ja710114r). But as far as I can see, these are not the bifurcated hydrogen bonds postulated by Sciortino et al. to play a role in molecular mobility in the liquid state (Nature 354, 218; 1991), where one proton binds to two oxygens. Rather, what we have here are simply oxygen atoms linked to two protons via H-bonding. Can we clean up the terminology please?
A paper by Masahide Terazima at Kyoto and colleagues offers evidence for the role of hydrophobic interactions in light switching of the antirepressor AppA of Rhodobacter sphaeroides (P. Hazra et al., J. Phys. Chem. B 112, 1494-1501; 2008. This molecule forms a dimer when its photosensitive BLUF domain is activated by blue light, and this photoactivated state then represses expression of genes involved in photosynthesis. It’s a rather subtle example of hydration changes inducing a biological behaviour.
K. A. Dill, T. M. Truskett, V. Vlachy & B. Hribar-Lee, Annu. Rev. Biophys. Biomol. Struct. 34, 173-199 (2005).
(Get it here.)
The other is Martin Chaplin’s paper ‘Do we underestimate the importance of water in cell biology?’, which, as the title implies, provides a much briefer overview of most of the issues I discuss in my review and carries the same basic message:
M. F. Chaplin, Nature Rev. Mol. Cell Biol. 7, 861-866 (2006).
(Get it here.)
Apologies for these omissions.
Moving on to things new… David Chandler’s comments on the mechanism of dewetting-induced hydrophobic assembly in my last post are expanded on in some detail in a new paper (A. P. Willard & D. Chandler, J. Phys. Chem. B doi:10.1021/jp077186+). They argue that the motions of the hydrophobic solutes are such that the basic cavitation process to form the ‘vapour bridge’ can have zero activation energy.
One of my favourite papers of the moment comes from Martina Havenith at Bochum and colleagues (S. Ebbinghaus et al., PNAS 104, 20749-20752; 2007). They have used terahertz spectroscopy and MD simulations to probe the hydration layer around proteins, in particular to estimate how thick it is. They find that differences in correlated water motions, relative to the bulk, extend to more than 2 nm from the protein surface. It’s a remarkable and important demonstration of the extra ‘reach’ that solvation affords biological macromolecules, and really makes the case for why the hydration layer needs to be considered in some sense a part of the molecule it encompasses, making them fuzzy-edged entities with a sphere of influence that stretches well beyond the apparent surface.
Martina and her colleagues have also looked at how this solvation structure is altered by mutations and by pH (S. Ebbinghaus et al., JACS doi:10.1021/ja0746520; paper here). They find that a single mutation of the five-helix bundle lambda*[6-85], replacing a glutamine side chain with aromatic residues, significantly reduces the reach of the perturbation to the solvation water. This distance is also reduced when the wild-type protein is denatured at pH 2. It will be interesting to know if both are general effects, implying that proteins are somehow optimized to induce maximum restructuring of the solvent.
Bertil Halle has sent me a preprint of a paper just accepted in PNAS, in which he along with Johan Qvist and Monika Davidovic at Lund, and Donald Hamelberg at UCSD, report a wholly water-free large hydrophobic cavity in bovine beta-lactoglobulin. This cavity, called the calyx and acting as a binding site for fatty acids and other nonpolar ligands, has a volume of 315 cubic Å. The authors contrast this with the interior of carbon nanotubes, which is nominally hydrophobic but threaded by water chains. It shows just how amazingly dry nature can keep itself when the need arises.
Bertil also has a new paper) with Erik Persson describing how magnetic relaxation dispersion studies of water molecules buried inside proteins can provide a probe of ns- to ms-timescale protein dynamics (E. Persson & B. Halle, JACS 130, 1774-1787; 2008).
Talking of water in nanotubes, Hideki Tanaka and his colleagues at Okayama University have ised MD simulations to map out the complete phase diagram of water in nanotubes at atmospheric pressure for diameters up to 1.7 nm (D. Takaiwa et al., PNAS 105, 39-43; 2008; paper here). They find at least nine different ice phases, each apparently adapting to the confined space in a way that maximizes the number of hydrogen bonds. They say that the confined liquid water doesn’t show a density maximum above freezing point, and that it shrinks on freezing. Nor is freezing necessarily a first-order transition here. All a rather beautiful picture of how profoundly confinement can alter water’s properties.
There’s a curious paper in Langmuir (A. P. Sommer, A. Caron & H.-J. Fecht, Langmuir 24, 635-636; 2008) claiming that ‘ordered interfacial water’ near hydrophobic and hydrophilic surfaces can be tuned with laser light, and that the light causes an increase in fluidity, presumed (as far as I can make out) to be due to depletion of the ‘ordered’ layer, in the hydrophilic case. I’m left wondering whether there is really any direct evidence for ‘increased ordering’ in these interfacial layers, and what precisely that means here. Something interesting seems to be happening, but I don’t think it’s clear what it is.
Aizhuo Liu et al. in Michigan report what they call ‘bifurcated’ hydrogen bonds in proteins, using isotope substitution studied with NMR (A. Liu et al., JACS doi:10.1021/ja710114r). But as far as I can see, these are not the bifurcated hydrogen bonds postulated by Sciortino et al. to play a role in molecular mobility in the liquid state (Nature 354, 218; 1991), where one proton binds to two oxygens. Rather, what we have here are simply oxygen atoms linked to two protons via H-bonding. Can we clean up the terminology please?
A paper by Masahide Terazima at Kyoto and colleagues offers evidence for the role of hydrophobic interactions in light switching of the antirepressor AppA of Rhodobacter sphaeroides (P. Hazra et al., J. Phys. Chem. B 112, 1494-1501; 2008. This molecule forms a dimer when its photosensitive BLUF domain is activated by blue light, and this photoactivated state then represses expression of genes involved in photosynthesis. It’s a rather subtle example of hydration changes inducing a biological behaviour.
Tuesday, January 22, 2008
Updates to the review
Inevitably, my review article has sins of omission and miscomprehension. I hope to put these right as they are pointed out to me.
One of the more serious is that I attributed to Meyer et al. [PNAS 102, 6839; 2005] the observation that a long-ranged electrostatic attraction can be established between two plates coated with lipids due to delamination of the monolayer and the formation of charged patches. This observation was in fact first reported by Jacob Klein and his coworkers in Phys. Rev. Lett. 96, 038301 (2006) and J. Phys. Chem. B 109, 3832-3837 (2005), though that work was overlooked in the Meyer et al. paper.
David Chandler has explained to me in more detail what is involved in the dewetting transition that he has postulated to occur as hydrophobic surfaces come together [Lum et al., J. Phys. Chem. B 103, 4570; 1999]. This transition has a signature that has not been necessarily sought in some of the simulations of protein aggregation looking for this effect, for example those by Bruce Berne’s group. David says:
“Bruce Berne is doing fine work. The empirical results he has collected are significant, and they are instructive when viewed in context. Problems can arise when the context is misunderstood, as I think they have been in some of Bruce’s writings. Case in point is that the ‘de-wetting’ mechanism of hydrophobic collapse does NOT require the presence of a vapor bubble BEFORE the collapse occurs, though that chronology is what Bruce takes to be the signature of the effect. Rather, an extended hydrophobic surface creates a loose fluctuating water interface. When the surface attracts that interface, the average interface position is close to the surface (i.e., no ‘vapor’ is explicitly seen). But that’s the average. More significantly, because the surface is soft (i.e., can fluctuate with little free energy cost), it becomes possible for water to move aside and thus possible for two hydrophobic surface to collapse upon one another. Consistent with this statement is that ensembles of trajectories and free energy functions show that the ‘reaction’ coordinate for hydrophobic assembly of two extended hydrophobic surfaces, whether idealized or ‘realistic’, has a significant contributor from water dynamics. That effect is the story of de-wetting that I have been trying to explain in my papers. I don’t think subsequent work has demonstrated this idea to be of limited applicability, though I do think many folks have misinterpreted what I have said. In a nutshell: in the matter of what liquid water does to make things happen, it’s the fluctuations that matter.”
Other papers relevant to the general topic of water in molecular biology that have been brought to my attention are:
A. Y. Mulkidjanian & D. A. Cherepanov, “Probing biological interfaces by tracing proton passage across them”, Photochem. Photobiol. Sci. 5, 577-587 (2006)
A. Y. Mulkidjanian, J. Heberle & D. A. Cherepanov, “Protons @ interfaces: Implications for biological energy conversion”, Biochim. Biophys. Acta 1757, 913-930 (2006)
J. Dzubiella, J. M. J. Swanson & J. A. McCammon, “Coupling nonpolar and polar salvation free energies in implicit solvent models”, J. Chem. Phys. 124, 084905 (2006)
L.-T. Cheng, J. Dzubiella, J. A. McCammon & B. Li, “Application of the level-set method to the implicit salvation of nonpolar molecules”, J. Chem. Phys. 127, 084503 (2007)
X. Gong, J. Li, H. Lu, R. Wan, J. Li, J. Hu & H. Fang, “A charge-driven molecular water pump”, Nature Nanotechnol. 2, 709-712 (2007)
There is also a nice crop of new papers that I should mention:
S. Joseph & N. R. Aluru, “Why are carbon nanotubes fast transporters of water?”, Nano. Lett. doi:10.1021/nl072385q (2008) [the answer is attributed to the presence of a depletion layer of water at the interface with the nanotube wall]
C. F. Lopez, R. K. Darst & P. J. Rossky, “Mechanistic elements o protein cold denaturation”, J. Phys. Chem. B doi:10.1021/jp075928t (2008) [in a nutshell: “low temperature leads to solvent-induced packing effects at the protein surface, and this more favourable water-protein interaction in turn destabilizes the overall protein structure”]
M. Lagi, X. Chu, C. Kim, F. Mallamace, P. Baglioni & S.-H. Chen, “The low-temperature dynamic crossover phenomenon in protein hyration water: simulations vs experiments”, J. Phys. Chem. B doi:10.1021/jp710714j (2008) [more on the explanation for the 220K dynamical transition of proteins in terms of the residual influence of a liquid-liquid critical point, an idea developed previously by these authors]
H. Chen, Y. Moreau, E. Derat & S. Shaik, “Quantum mechanical/molecular mechanical study of mechanisms of heme degradation by the enzyme heme oxygenase: the strategic function of the water cluster”, J. Am. Chem. Soc. doi:10.1021/ja076679p (2008) [more on the roles of ‘bound water’ in enzymatic catalysis]
D. K. Hore, D. S. Walker & G. L. Richmond, “Water at hydrophobic surfaces: when weaker is better”, J. Am. Chem. Soc. doi:10.1021/ja0755616 (2008) [uses MD simulations to conclude that “the degree of water structuring in the immediate vicinity of the oil-water junction is highest when the hydrophobic phase is least polar”]
One of the more serious is that I attributed to Meyer et al. [PNAS 102, 6839; 2005] the observation that a long-ranged electrostatic attraction can be established between two plates coated with lipids due to delamination of the monolayer and the formation of charged patches. This observation was in fact first reported by Jacob Klein and his coworkers in Phys. Rev. Lett. 96, 038301 (2006) and J. Phys. Chem. B 109, 3832-3837 (2005), though that work was overlooked in the Meyer et al. paper.
David Chandler has explained to me in more detail what is involved in the dewetting transition that he has postulated to occur as hydrophobic surfaces come together [Lum et al., J. Phys. Chem. B 103, 4570; 1999]. This transition has a signature that has not been necessarily sought in some of the simulations of protein aggregation looking for this effect, for example those by Bruce Berne’s group. David says:
“Bruce Berne is doing fine work. The empirical results he has collected are significant, and they are instructive when viewed in context. Problems can arise when the context is misunderstood, as I think they have been in some of Bruce’s writings. Case in point is that the ‘de-wetting’ mechanism of hydrophobic collapse does NOT require the presence of a vapor bubble BEFORE the collapse occurs, though that chronology is what Bruce takes to be the signature of the effect. Rather, an extended hydrophobic surface creates a loose fluctuating water interface. When the surface attracts that interface, the average interface position is close to the surface (i.e., no ‘vapor’ is explicitly seen). But that’s the average. More significantly, because the surface is soft (i.e., can fluctuate with little free energy cost), it becomes possible for water to move aside and thus possible for two hydrophobic surface to collapse upon one another. Consistent with this statement is that ensembles of trajectories and free energy functions show that the ‘reaction’ coordinate for hydrophobic assembly of two extended hydrophobic surfaces, whether idealized or ‘realistic’, has a significant contributor from water dynamics. That effect is the story of de-wetting that I have been trying to explain in my papers. I don’t think subsequent work has demonstrated this idea to be of limited applicability, though I do think many folks have misinterpreted what I have said. In a nutshell: in the matter of what liquid water does to make things happen, it’s the fluctuations that matter.”
Other papers relevant to the general topic of water in molecular biology that have been brought to my attention are:
A. Y. Mulkidjanian & D. A. Cherepanov, “Probing biological interfaces by tracing proton passage across them”, Photochem. Photobiol. Sci. 5, 577-587 (2006)
A. Y. Mulkidjanian, J. Heberle & D. A. Cherepanov, “Protons @ interfaces: Implications for biological energy conversion”, Biochim. Biophys. Acta 1757, 913-930 (2006)
J. Dzubiella, J. M. J. Swanson & J. A. McCammon, “Coupling nonpolar and polar salvation free energies in implicit solvent models”, J. Chem. Phys. 124, 084905 (2006)
L.-T. Cheng, J. Dzubiella, J. A. McCammon & B. Li, “Application of the level-set method to the implicit salvation of nonpolar molecules”, J. Chem. Phys. 127, 084503 (2007)
X. Gong, J. Li, H. Lu, R. Wan, J. Li, J. Hu & H. Fang, “A charge-driven molecular water pump”, Nature Nanotechnol. 2, 709-712 (2007)
There is also a nice crop of new papers that I should mention:
S. Joseph & N. R. Aluru, “Why are carbon nanotubes fast transporters of water?”, Nano. Lett. doi:10.1021/nl072385q (2008) [the answer is attributed to the presence of a depletion layer of water at the interface with the nanotube wall]
C. F. Lopez, R. K. Darst & P. J. Rossky, “Mechanistic elements o protein cold denaturation”, J. Phys. Chem. B doi:10.1021/jp075928t (2008) [in a nutshell: “low temperature leads to solvent-induced packing effects at the protein surface, and this more favourable water-protein interaction in turn destabilizes the overall protein structure”]
M. Lagi, X. Chu, C. Kim, F. Mallamace, P. Baglioni & S.-H. Chen, “The low-temperature dynamic crossover phenomenon in protein hyration water: simulations vs experiments”, J. Phys. Chem. B doi:10.1021/jp710714j (2008) [more on the explanation for the 220K dynamical transition of proteins in terms of the residual influence of a liquid-liquid critical point, an idea developed previously by these authors]
H. Chen, Y. Moreau, E. Derat & S. Shaik, “Quantum mechanical/molecular mechanical study of mechanisms of heme degradation by the enzyme heme oxygenase: the strategic function of the water cluster”, J. Am. Chem. Soc. doi:10.1021/ja076679p (2008) [more on the roles of ‘bound water’ in enzymatic catalysis]
D. K. Hore, D. S. Walker & G. L. Richmond, “Water at hydrophobic surfaces: when weaker is better”, J. Am. Chem. Soc. doi:10.1021/ja0755616 (2008) [uses MD simulations to conclude that “the degree of water structuring in the immediate vicinity of the oil-water junction is highest when the hydrophobic phase is least polar”]
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