An empty binding site
Derek Lowe has a blog post that brought to my attention a very interesting paper. The authors show the extreme case of a completely dehydrated empty binding site for the large nonpolar binding cavity in bovine β-lactoglobulin. They state it is not a matter of undetectable spatially delocalized waters — they have used techniques like water 17O and 2H magnetic relaxation dispersion (MRD), 13C NMR spectroscopy, molecular dynamics simulations, and free energy calculations to establish the absence of water from the binding cavity. The site appears to be empty — plain old vacuum. Based on the comments on Derek’s blog, many people find this very intriguing — just like myself.
I have seen many protein structures in the PDB with significant empty gaps, but I always assumed there must be water there with high enough entropy not to be “visible” in the electron density map of the X-ray. But this paper raises the question whether it is such a rare case or perhaps it is happening on smaller scale quite regularly, i.e. there may be smaller gaps occuring with a significant probability in most hydrophobic pockets. Since this happened even in the crystal, during the solvated dynamic environment it should happen more often for short time periods. What would that mean for binding energy estimation, scoring ? We need to re-think the the de-solvation energy and entropy estimation components. The implicit homogenous solvent models seem to be even more inadequate than we suspected (not that I trusted them too much anyway).
OK, maybe I should not get carried away, it is only one very strange case so far. But we better keep an eye open for similar reports…
ZZ