Coarse-grained models

More on the mechanisms of urea-induced protein denaturation, this time from Ruhong Zhou at IBM and his colleagues in Beijing (M. Gao et al., J. Phys. Chem. B 114, 15687; 2010 – paper here). In simulations, they look at the populations of water and urea molecules around each residue in hen egg-white lysozyme, and find that some of the hydrophobic core residues stay virtually dry as unfolding proceeds in 8M urea. Moreover, the urea molecules are bound preferentially to uncharged rather than to charged residues. So the picture is that the protein swells to a molten globule state while keeping largely dry inside, because it is the urea rather than water that penetrates. this may not be a wholly general order of events, however – depending on the detailed shape and structure of the protein, water might sometimes penetrate first, as found for example by Bennion and Daggett (PNAS 100, 5142; 2003).

John Klassen and colleagues at the University of Alberta present an interesting comparison of protein-ligand dissociation constants in the hydrated and dehydrated states (L. Liu et al., JACS 132, 17658; 2010 – paper here). The latter are obtained from gas-phase measurements at 25-66 C. The kinetic stability of the associated state is significantly reduced in the hydrated phase: water stabilizes the dissociative transition state and might thereby be considered a kind of lubricant that facilitates the departure of the ligand.

David Beauchamp and Mazdak Khajehpour predicate their study of water-water interactions on enzyme activity with the supposition that the hydrogen-bond distribution in pure water is bimodal, with bonds that are high- and low-angle (J. Phys. Chem. B 10/1021/jp107556s – paper here). They say this is supported by some simulations, and that it is consistent with the (contentious) two-state model of the liquid. They also say that salts have the ability to perturb this distribution. OK… so given these assumptions, they see what added salts do to the activity of ribonuclease t1, and say that their spectroscopic and kinetic results are consistent with the notion that salts that promote the high-angle bonds stabilize the more compact and less active forms of the enzyme. Interesting ideas, but it seems a big leap from the data to the microscopic interpretation.

I recently described work by Martin Gruebele, Martina Havenith and colleagues on the mechanism of antifreeze glycoproteins, in which they argued that the biomolecules can effect long-range changes in water dynamics to inhibit freezing (S. Ebbinghaus et al., JACS 132, 12210; 2010). The authors now report similar findings for a 37-residue alpha-helical antifreeze protein from winter flounder (S. Ebbinghaus et al., Biophys. J. Biophys. Lett. in press). The find using CD and FRET on native and mutant versions that the antifreeze activity seems to be connected to a kinking of the helix, and that this is coupled to a suppression of bulk-like dynamics in the solvation water over a range of at least 3 nm, as indicated by THz spectroscopy.

Years ago, Royer et al. showed that a group of water molecules at the interface between the subunits of the dimeric haemoglobin of Scapharca clams seem implicated in the molecule’s allosteric cooperativity (Royer et al., PNAS 93, 14526; 1996). David Leitner and colleagues at the University of Nevada at Reno now look in detail at the dynamics of this cluster of waters using MD simulations based on the crystal structures (R. Gnanasekaran et al., J. Phys. Chem. B 114, 16989; 2010 – paper here). They find that those in the oxy form (11 molecules) exhibit slower relaxation than those (17) in the deoxy form, and that the water cluster, although rather static on ps timescales, can enhance energy transport across the interface of the subunits via vibrations.

The close and reciprocal interactions of water and protein dynamics, especially at low temperatures, seems to be echoed in the case of hydrated lipid bilayers, according to Peter Berntsen and colleagues at Chalmers University in Göteborg (J. Phys. Chem. B 10.1021/jp110899j – paper here). They have used dielectric rexlaxation measurements below 250 K to show that at low temperatures the water dynamics becomes increasingly dominated by the movements of the lipids, and is super-Arrhenius-like at low hydration levels.

Fast proton transport along peptide backbones can be assisted by water bridges, according to ab initio calculations by Po-Tuan Chen of the National Taiwan University of Science and Technology and colleagues (J. Phys. Chem. B 10.1021/jp107219r – paper here). They say that a two-molecule water bridge can make the transport between two adjacent carbonyl oxygens almost barrierless.

In a preprint (not sure where it is destined, but it looks like JCP format), David Chandler and his coworkers present a coarse-grained lattice model to implement the Lum-Chandler-Weeks dewetting theory of hydrophobic interactions (P. Varilly et al., arxiv: 1010.5750 – paper here). The model captures the essential features of the model at far less computational cost than full MD simulations, in particular modelling the solvent fluctuations that are essential for the dewetting mechanism.

With much the same objective of computational cheapness, Ken Dill at UCSF and colleagues present a new solvation model that they call semi-explicit self-assembly (C. J. Fennell et al., PNAS 108, 3234; 2011 – paper here). They basically construct a solute’s solvation shell as some combination of pre-computed solvation shells for simple spheres in explicit TIP3P water. They have so far only tested it here on simple small molecules such as sugars.

And Valeria Molinero and colleagues at the University of Utah have a coarse-grained model of DNA solvation with explicit water and ions (R. C. DeMille et al., J. Phys. Chem. B 115, 132; 2011 – paper here). It reproduces base-pair specificity and is computationally faster by two orders of magnitude than atomistic simulations.

There is a curious paper in Nature Structural and Molecular Biology by Nathaniel Nucci and colleagues at the University of Pennsylvania (NSMB 18, 245; 2011 – paper here) on an NMR technique to identify residence times of specific clusters of water molecules around proteins. I say curious, because these useful results are presented, particularly in a News & Views article in Nature (V. J. Hilser, Nature 469, 166; 2011 – paper here), as “challenging current dogma about protein hydration”. It seems this challenge comes from the fact that the results show that not all ‘bound’ water exchanges slowly with the surrounding solvent. But a wide range of exchange times is surely already well established, especially from simulations – the old crystallographic picture in which ‘hydration water’ is all securely bound and long-lived seemed long dead. Still, it is interesting that Nucci et al., whose method relies on confining the proteins (here ubiquitin) within reverse micelles to slow the hydration dynamics, found that water molecules with similar residence times seem to cluster on the protein surface, so that the molecules in each cluster form independent networks which exhibit intra-cluster cooperativity.

In another preprint, Giancarlo Franzese and colleagues at the University of Barcelona offer something of a mini-review of hydration structure and dynamics at protein surfaces, along with some Monte Carlo simulations that investigate cooperativity and dynamical transitions of a water monolayer hydrating a protein surface at low temperatures (arxiv preprint 1010.4984; paper here).

On the still-evolving picture of pure liquid water: Alessandro Cunsolo at Brookhaven and his colleagues study it using QENS to look at single-particle diffusion rates at 200 MPa as a function of temperature, and find that their results point to the proposed existence of a second critical point at about 220 K, and of the Widom line which ends at this point (J. Phys. Chem. B 114, 16713; 2010 – paper here).

Meanwhile, Richard Henchman and Sheeba Jem Irudayam of Manchester University in the UK propose a ‘topological’ definition of hydrogen bonding in water that offers a new description of water structure and dynamics (investigated in simulations using TIP4P/2005 water) based on the character of the H-bond network (J. Phys. Chem. B 10.1021/jp105381s – paper here). They say that in this description almost all the water molecules are H-bonded and that there are an appreciable number of ‘defects’ in which molecules are acceptors for one (trigonal) and three (trigonal bipyramidal) hydrogens rather than two.