Smooth folding

A paper in the forthcoming issue of PNAS (104, 6206; doi/10.1073/pnas.0605859104) by Peter Tieleman’s group at the University of Calgary looks at how to reconcile the energy-funnel picture of protein folding with the fact that there are likely to be significant enthalpic barriers to the folding process. They use simulations of the association of two polyalanine and two polyleucine alpha-helices to figure out whether enthalpic barriers exist (they do), and why. It seems they arise in this case from the fact that, as the chains approach, they must become desolvated before there is a compensating enthalpic gain from strong helix-helix interaction. (Interestingly, the researchers see no dewetting transition as the helices approach, of the sort predicted by Lum, Chandler and Weeks (J. Phys. Chem. B 103, 4570-4577; 1999), but only ‘steric dewetting’ when there is simply no longer space to fit in a layer of water. This contrasts with the simulations of hydrophobic plates by Bruce Berne mentioned in my previous post (JACS asap doi:10.1021/ja068305m), where dewetting does feature. It is possible that this might be rather sensitive to the precise geometry, size and hydrophobicity of the two surfaces.) The enthalpic energy barrier is, however, largely compensated by the gain in solvent entropy on desolvation, leading to a free-energy barrier that is very small (for poly-A) or non-existent (for poly-L). Thus, the idea of a relatively smooth free-energy funnel is recovered.

I’ve now had a better look at the Berne paper. It suggests that Hofmeister effects are indeed complicated, and not best explained by a simplistic structure-making/breaking model. In the case of the association of nanoscale hydrophobic surfaces, the effect of ions depends on whether or not they accumulate preferentially at the surfaces. High-charge-density ions induce salting-out (reducing the solubility of hydrophobes) via an entropic effect due to preferential exclusion of ions from the interfaces. Medium-charge-density ions induce salting in because of a different entropic effect, due to strong hydration of the ions and a consequent reduction in solvent entropy when the ions, preferentially adsorbed at the surfaces, are expelled as the surfaces associate (I think I’ve got that right). But low-charge-density ions cause salting in enthalpically, since they bind to the surfaces and lower the surface tension of the plate-water interface, thus lowering the enthalpy of association. As if this isn’t complicated enough, Berne and colleagues say that something quite different applied for electrolytes and small hydrophobic particles (see Zangi & Berne, J. Phys. Chem. B 110, 22736-22741; 2006). Hmm.

Not strictly related to biochemistry, but Rudy Marcus and Yousung Jung have just published a proposed explanation for why there is a rate acceleration of certain organic reactions, particularly those associated with ‘click chemistry’, at the interface of water and an organic phase: see JACS asap doi:10.1021/ja068120f.