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...