Tuesday, September 18, 2007

A(nother) word on urea

I discovered at the 2007 Halophiles meeting at the University of Essex earlier this month that the mechanism of protein denaturation by urea is still a matter of debate. That’s not, perhaps, terribly surprising in view of the fact that even the hydration structure of urea itself is not certain, as earlier posts have mentioned. Jose Manuel Hermida-Ramon at the University of Vigo in Spain and coworkers add a contribution to this debate in J. Phys. Chem. B [doi:10.1021/jp073579x]. They use quantum-chemical calculations to deduce the structure of the hydrated urea molecule, and say that it is ill-defined: the molecule is very floppy, because the transition from a planar to a non-planar structure has an activation energy comparable to the room-temperature thermal energy. However, they say that urea might adopt a fixed, or less flexible, structure, as it approaches a protein surface.

Wayne Bolen and colleagues at the University of Texas Medical Branch at Galveston have attempted to tease out the ways that urea interacts with peptide residues when this happens [M. Auton et al., PNAS doi:10.1073/pnas.0706251104]. Using thermodynamic data, they say that, contrary to some previous views, the key interactions are not with nonpolar side chains, but involve the peptide backbone itself, and that these latter interactions are what drives denaturation. No doubt we’ll be hearing more about this issue.

The question of dewetting of protein surfaces in folding and aggregation also rumbles on. Following on from the Lum/Chandler/Weeks idea of dewetting of large hydrophobes and a consequent crossover length in the mechanism of hydrophobic attraction [K. Lum et al., J. Phys. Chem. B 103, 4570; 1999; D. Chandler, Nature 437, 640; 2005], Jeremy Smith at Heidelberg and colleagues have looked at whether there is ‘dewetting’ around hydrophobic residues of smaller peptides [I. Daidone et al., PNAS doi:10.1073/pnas.0701401104]. They say that for a 14-residue beta-hairpin peptide, conformers that expose significant amounts of hydrophobic surface have a lower hydration density than those that don’t, and that as a consequence, “dehydration-driven solvent exposure of hydrophobic surfaces may be a significant factor determining peptide conformational equilibria.” Which looks fine as far as it goes, but I can’t obviously see if this addresses the question of whether there is an abrupt, cooperative drying transition during folding, as seemed to be a central feature of the LCW model…

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