Monday, June 19, 2017

Chiral water in DNA's hydration shell

In a clever study of DNA hydration using SFG spectroscopy, Poul Petersen and his coworkers have found that the chiral spine of hydration in the minor groove, inferred from oxygen locations for hydrated crystalline DNA by Dickerson and collaborators in the 1980s, exists also in aqueous solution under ambient conditions, and entails orientational ordering of the hydrogen bonds in the single-file water chain that fits into this narrow groove (M. L. McDermott et al., ACS Centr. Sci. 10.1021/acscentsci.7b00100; 2017 – paper here). I wrote a news story for Chemistry World on this work (here).

I applaud the ambition of Modesto Orozco of the Barcelona Institute of Science and Technology and colleagues in writing a paper called “The multiple roles of waters in protein solvation” (A. Hospital et al., JPCB 121, 3636; 2017 – paper here). There’s a title guaranteed to say to me “Read this now!” And the ambition continues in the extent of the systems they investigate with MD: a range of proteins, at a range of temperatures, some denatured, some with crowding agents, some with high concentrations of urea. They say that the results illustrate “the dramatic plasticity of water, and its chameleonic ability to stabilize proteins under a variety of conditions”, which seems a fair way to summarize the matter. I’m not sure I see any surprises here, and the denaturant effects of urea are discussed with something of a “water structure” flavour, but it’s a kind of snapshot of the sorts of things hydration water gets up to.

A more specific study of protein hydration dynamics is described by Dongping Zhong and colleagues at Ohio State University, who use tryptophan as the reporter group to characterize the dynamics at 17 sites on the surface of the β-barrel protein rat liver fatty acid binding protein (J. Yang et al., JACS 139, 4399; 2017 – paper here). They observe three quite distinct dynamical timescales. The water in the outer hydration layer is bulk-like, relaxing quickly (hundreds of fs). For the inner layer, reorientational motion happens on a few-ps timescale, while larger-scale network restructuring takes many tens of ps. The last of these seem to drive protein fluctuations on comparable timescales.

The dynamics of the protein hydration layer are examined by Biman Bagchi and colleagues of the Indian Institute of Science in Bangalore by calculating those around residues (Trp, Tyr, His) previously used as natural probes in spectroscopic studies (S. Mondal et al., arxiv preprint 1701.04861). They find a range of different timescales, including accelerated as well as retarded rotations. Since NMR measurements give average values, these findings might explain the apparently discrepancy between such studies and those (such as Zewail’s) that focus on specific residues. The protein side-chain dynamics seem particularly to influence the slow solvation component.

The role of hydration in the protein dynamical transition around 230 K has been widely debated. Prithwish Nandi and Niall English at University College Dublin find in MD simulations of lysozyme that the protein and hydration water dynamics seem to be correlated up to about 285 K, at which point the protein-water hydrogen-bond network becomes too disrupted to sustain the coupling (JPCB 120, 12031; 2016 – paper here).

However, the whole notion of coupling between the protein and hydration dynamics in the vicinity of the ~200-220 K dynamical transition is challenged by Antonio Benedetto of University College Dublin on the basis of elastic neutron-scattering from lysozyme (arxiv preprint 1705.03128). Specifically, the water begins to relax at 179 K, while the protein doesn’t do so until 195 K. It seems puzzling, and no explanation is advanced here for the discrepancy with a considerable body of earlier results.

I missed previously this nice paper from H. F. M. C. Martiniano and Nuno Galamba in Lisbon on the structure and dynamics of water around a hydrophobic amino acid (PCCP 18, 27639; 2016 – paper here). It reports MD simulations of the hydration of valine, and distinguishes between two populations of water molecules in the hydration shell: those that have have four and less than four neighbours. The latter, they say, have faster librational dynamics than bulk water and faster orientational dynamics than four-coordinated “tetrahedral” water. Meanwhile, four-coordinate water in the hydration shell are “more tetrahedral” than bulk water at all temperatures. It would seem, then, that this work argues the case for “tetrahedrality” as a useful concept for characterizing water structure, while advising caution about how it is used and interpreted for the bulk.

Guanidinium is a complicated osmolyte. It can act as both a protein denaturant and stabilizer, depending on the counteranion. Jan Heyda at the Institut für Weiche Materie und Funktionale Materialien in Berlin and colleagues have setout to understand why, using MD simulations and FTIR (J. Heyda et al., JACS 139, 863; 2017 – paper here). Their test peptide, an elastin-like polypeptide, was stabilized in the collapsed state by Gnd sulphate by an excluded volume effect (Gnd being depleted at the peptide/water interface). GndSCN was stabilizing at low concentrations thanks to Gnd+’s ability to crosslink the polymer chains, but at higher concentration it became a denaturant. GndCl, meanwhile, was a denaturant at all concentrations, since in this case partitioning of the chloride to the polymer surface enables recruitment of Gnd+ to the surface too, where it stabilizes the unfolded state. A very graphic example of how the details of direct interactions between polymer, anion, cation (and potentially water) all matter in figuring out what is going on.

Essentially the same team – which includes Paul Cremer, Joachim Dzubiella and Pavel Jungwirth – have put together a review of such ion-specific effects that, it seems to me, will be the go-to resource for this field for some time to come (H. I. Okur et al., JPCB 121, 1997; 2017 – paper here). I need say no more; if you want to understand how the thinking on Hofmeister has developed over the past several years, this is where to come.

Does water play the role of reactant in O-O bond formation in photosystem II? That idea has been suggested, water acting as a nucleophile that attacks a terminal oxo group. But Per Siegbahn of Stockholm University uses DFT calculations to determine the free-energy barriers for the six most plausible modes of attack and finds that these barriers are all too high (PNAS 114, 4966; 2017 – paper here) – a notion put forward previously but here refined using improved structural data and computational methods.

I didn’t even know that lipid bilayers, like proteins, show a dynamical transition around 200 K or so. But it seems they do. V. N. Syryamina and S. A. Dzuba of the Russian Academy of Sciences in Novosibirsk have studied thus for two types of phosphocholine bilayers in water using a technique (also new to me) called electron spin echo envelope modulation spectroscopy to follow hydrogen (deuterium) motions (JPCB 121, 1026; 2017 – paper here). They find that the dynamical transition in the bilayer interior at 188 K is accompanied by the onset of water motion in the first hydration layer, and that another transition around 100 K is accompanied by restricted reorientational motions of water. What I can’t tell from these results is whether there is any sign of slaving of water to lipid dynamics or vice versa.

I’m not going to pretend to understand the Bayseian model used by Nathan Baker of PNNL in Washington and colleagues to estimte small-molecule solvation free energies (L. J. Gosink et al., JPCB 121, 3458; 2016 – paper here). But it’s basically a method for aggregating many other calculational procedures, and seems to work better than any such techniques in isolation.

Mihail Barbiou of the European Institute of Membranes in Montpellier and colleagues have used artificial water channels in liposomes, made from stacked imidazoles, to investigate water transport along water wires, analogous to those that thread through aquaporins (E. Licsandru et al., JACS 138, 5403; 2016 – paper here). The channels can conduct around a million water molecules per second, a rate two orders of magnitude greater than AQPs, and also conduct protons (but not other ions) efficiently. The chirality of the channels seems to be important for producing strong dipolar orientation in the water wire. Let me also draw attention to Mihail’s nice review of artificial water channels, which includes this example, in Chem. Commun. 52, 5657 (2016) (paper here).

The water channel in stacked imidazoles.

More on water confined in pores: in MD simulations, Xiao Cheng Zeng at the University of Nebraska and colleagues see low- and high-density liquid states of water within single-walled carbon nanotubes of 1.25 nm diameter at ambient temperature (K. Nomura et al., PNAS 114, 4066; 2017 – paper here). The two phases are, however, separated by a hexagonal “tubular ice” phase (which has already been observed experimentally).

How does water freeze at liquid-vapour interfaces? Specifically, does the interface itself nucleate or suppress freezing? That’s a question relevant to a host of real-world phenomena such as ice nucleation in clouds and other atmospheric processes, but it’s been hard to study experimentally, but Amir Haji-Akbari and Pablo Debenedetti in Princeton study it computationally in a free-standing 4-nm-thick water nanofilm (PNAS 114, 3316; 2017 – paper here). Although the rate of ice nucleation in this confined geometry is seven orders of magnitude greater than that in the bulk, nucleation doesn’t start in the surface layers but rather in the (non-bulk-like) interior of the film, where the conditions favour the formation of “double-diamond” water cages that serve as the seeds for the nucleation and growth of cubic ice.

And here’s a truly surprising thing, discovered by Pablo and Amir in another paper working with Elia Altabet: making hydrophobic plates confining water to a space just over 1 nm wide more flexible by just an order of magnitude decrease in the modulus increases the evaporation rate by nine orders of magnitude, and decreases the condensation rate from the vapour by no less than 24 orders of magnitude, changing the timescale of the process from nanoseconds to tens of millions of years (Y. E. Altabet et al., PNAS 114, E2548; 2017 – paper here). This, at any rate, is what is implied by simulations for plates 3 nm square. Evaporation proceeds via the formation of bubbles at the surfaces that then grow and coalesce to form a gap-spanning cavity. For stiff plates this coalescence is rare, and so is the subsequent growth of the cavity above the critical size for nucleation of the vapour phase. For softer, more flexible plates these configurations occur much more frequently. Such a sensitivity of a drying transition to subtle changes in the mechanical properties may well have implications for processes involving hydration changes at or close to membrane proteins, and could presumably have ramifications for materials design of surfaces on which protein adhesion needs to be controlled.

Optimization of lead compounds for drug discovery is a complicated business, and when this is done by empirical combinatorial screening, the results can sometimes be counterintuitive, with nonpolar groups in the ligand juxtaposed to polar groups in the target for example. Ariel Fernandez at the Argentine Institute of Mathematics and Ridgway Scott of the University of Chicago review a method for understanding some of those apparent conundrums that involves a consideration of the relevant hydration structures, and in particular the role of what Ariel calls dehydrons (water-exposed backbone hydrogen bonds, which lead to frustration in the hydrogen-bonding arrangements of adjacent water molecules) (Trends Biotechnol. 35, 490; 2016 – paper here). Their approach uses the WaterMap software to identify “hot” water molecules that might profitably be displaced by a ligand to increase the binding energy and drug specificity.

The hydrogen-bond network of pure water is of course riddled with defects which underpin fluctuations of the network. Because of topological constraints these tend to occur in correlated pairs. Ali Hassanali at the ASICTP in Trieste and colleagues have studied these correlations using ab initio modelling (P. Gasparotto et al., J. Chem. Theor. Comput. 12, 1953; 2016 – paper here). They say that the defect pairs have some similarities to those in solid states of water, and are rather insensitive to the details of the water potentials used.

One of water’s well known “anomalies” is the decrease in viscosity with increasing applied pressure, which seems to be a consequence of a collapse of the hydrogen bonding network. This effect is larger at low temperatures, but whether that trend continues into the supercooled region hasn’t been studied previously. Now Frédéric Caupin and colleagues at the University of Lyon have investigated this effect down to 244 K and for pressures of up to 300 MPa, and find that indeed the viscosity reduction can be dramatic – by as much as 42% (L. P. Singh et al., PNAS 114, 4312; 2017 – paper here). They argue that the results can be understood by invoking a two-state model under these conditions: a mixture of a high-density “fragile” liquid and a low-density “strong” liquid.

Finally, I have taken what I hope is a somewhat fresh look at the many roles of water in molecular biology in an article for PNAS, for a special issue on water (2017 – paper here), which I hope extends the general message of my 2008 Chem Rev article (paper here) using some more recent examples.

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