Lots to catch up on here, and while I’m not going to do that exhaustively now, here is an update to let you know that this blog will still be active in 2012.
I’ve recently written a News & Views article for Nature (478, 467; 2011 – here) about, among other things, the recent paper by George Whitesides’ group (PNAS 108, 17889; 2011 – paper here) on the hydrophobic effect in ligand binding – which, as discussed in the previous post, suggests that there is not any single ‘hydrophobic effect’ operating here, but a delicate and case-specific balance of enthalpic and entropic effects. They noted that in the example they studied, the ‘hydrophobic’ aspect of binding was driven largely by the enthalpic effect of displacing/rearranging water around nonpolar contacts. That notion is supported by a paper by Stephen Martin and colleages at the University of Texas at Austin, who find something rather similar for small peptide binding by the SH2 domain of the growth receptor binding protein Grb2 (J. M. Myslinski et al., JACS 133, 18518; 2011 – paper here). They say that increases in the nonpolar contact area don’t necessarily lead to entropic gains due to release of water, but have a primarily enthalpic influence on binding affinity.
How quickly drugs bind to their target molecules can have important pharmacological implications, but these kinetics are generally poorly understood, and thus to design rationally. Xavier Barril from the University of Barcelona and colleagues show using MD simulations that slow kinetics are often a consequence of the presence of buried polar atoms which form hydrogen bonds that are shielded from water, because of the slowness of dehydration/rehydration (P. Schmidtke et al., JACS ja207494u – paper here). In other words, the pace of events in binding can be set by the degree of water accessibility. They show that this effect can be predicted from structural data, and can thus potentially be accessible to design.
Knowing the hydration structure of proteins is important for small-/wide-angle X-ray scattering (SWAXS) studies of proteins not so much for its own sake but because the contribution of the solvent to the scattering must be subtracted in order to extract information about the protein secondary structure. It’s easy enough to extract the contribution of bulk water, but correcting for the scattering of the hydration shell is complicated. Tobin Sosnick and coworkers at the University of Chicago now show two ways to do this (J. J. Virtanen et al., Biophys. J. 101, 2061-2069; 2011 – paper here). One is to deduce the solvation structure by full MD simulations, which they say gives results that match the SWAXS data closely. But they have also developed a much more computationally less intense solvation model called HyPred, which gives a scattering profile that agrees well both with MD and with experiment.
Bernhardt Trout and his coworkers at MIT present an illustration of just how complex the interactons of proteins and ions can be (D. Shukla et al., JACS ja205215t – paper here). Complex ions such as guanidinium create a particularly intricate picture. Gdm+ can destabilize proteins via the formation of hydrogen bonds and electrostatic interactions, but when paired with an anion that is a hydrogen-bonding acceptor it can form clusters with the ions, which suppresses the effect. Molecules (such as arginine) with multiple Gdm+ groups are sometimes used to suppress protein aggregation, and can do so without compromising protein stability. Trout and colleagues investigate the effect of arginine oligomers (n=1-4) on protein aggregation and conformational stability for two different anions, chloride and sulphate. While monomeric arginine chloride is used as an aggregation suppressor, the n-mers only inhibit aggregation at low concentration – they actually accelerate it at moderate to high concentration. Meanwhile, the sulphates inhibit aggregation at all concentrations. And while the chlorides reduce protein stability, the sulphates enhance it. The researchers explain all this in terms of the balance between ion-ion and ion-protein interactions.
All this mirrors an increasing tendency to consider Hofmeister effects of ions on proteins in terms of direct interactions between the two species, rather than as indirect consequences of changes in hydration. Elena Algaer and Nico van der Vegt at the TU Darmstadt provide some support for this notion with a study of the salting-in and –out of small model amides by various sodium salts (J. Phys. Chem. B jp208583w – paper here). They say, for example, that the salting-in if NiPAM by NaI is mediated by interactions of iodide with the nonpolar groups. Such interactions also explain why, of all the salts studied, the iodide alone fails to induce hydrophobic collapse of polyNiPAM.
How does water permeate cell membranes? Its passage through the water-regulating membrane protein aquaporin is fairly well studied, but little is known about other water transporters. The bacterial sodium-galactose transporter vSGLT and its human homologue the sodium-glucose cotransporter hSGLT1 both have the potential to let water through. Jean-Yves Lapointe at the Université de Montréal and colleagues have used MC and MD simulations to show that indeed these protein pores can be filled with water (a pathway of about 100 molecules) which allows passive water permeation (L. J. Sasseville et al., Biophys. J. 101, 1887-1895; 2011 – paper here). This pathway depends on the proteins’ conformation: there is a constriction at one point which reduces the water bridge to a single-molecule chain which then ‘snaps’ at a ‘hydrophobic plug’, creating a 4.3 Å gap of low water density. But the resulting barrier to water permeation is conformation-dependent, and can be altered by varying the membrane potential. The passage of a sugar molecule also can bring water with it, but the mechanism of this is still open to debate.
Jhih-Wei Chu and colleagues at Berkeley conclude from MD simulations that the insolubility of cellulose in water is an entropic effect due primarily to the reduction of solvent entropy if the glucan chains in a fibril unravel (A. S. Gross et al., J. Phys. Chem. B 115, 13433; 2011 – paper here). There are some lessons here for how to solubilize cellulose in other solvents, such as ionic liquids.
Why and how do ions segregate at the air-water interface? This phenomenon seems well attested, with anions, especially large and polarisable ones, tending to accumulate at the interface. But the reason for this is still debated. Yi Qin Gao if the Beijing National Laboratory for Molecular Sciences and coworkers investigate the question with MD simulations, looking in particular at the differences in how anions and cations are solvated (L. Yang et al., J. Phys. Chem. B jp207652h – paper here). They argue that these differences are due to the charge distribution in the water molecules themselves, and that water can approach anions more closely than cations. They suggest that these differences in hydration account for why anions tend to populate the interface more readily.
And on the same topic, Pavel Jungwirth and colleagues have looked at how the hydration of guanidinium ions affects their orientation at the air-water interface (E. Wernersson et al., J. Phys. Chem. B jp207499s – paper here). Guanidinium is depleted at the interface, but the ions that do stay there are preferentially oriented parallel to the surface: in this configuration, it can sit at the surface without needing to break hydrogen bonds. Another way of looking at this is that the ions can take advantage of the deficit of hydrogen bonds between waters at the surface. The authors suggest that similar reasoning might account for the unexpected orientation of some arginine groups (with an analogous structure) in protein side chains.