Paper detail

Using schematic models to understand the microscopic basis for inverted solubility in $γ$D-crystallin

Inverted solubility--a crystal melting upon cooling--is observed in a handful of proteins, such as carbomonoxy hemoglobin and $γ$D-crystallin. In human $γ$D-crystallin, the phenomenon is associated with the mutation of the 23$^\mathrm{rd}$ residue, a proline, to a threonine, serine or valine. One proposed microscopic mechanism for this effect entails an increase in hydrophobicity upon mutagenesis. Recent crystal structures of a double mutant that includes the P23T mutation allows for a more careful investigation of this proposal. Here, we first measure the surface hydrophobicity of various mutant structures of this protein and determine that it does not discernibly increase upon the mutating the 23$^\mathrm{rd}$ residue. We then investigate the solubility inversion regime with a schematic patchy particle model that includes one of three models for temperature-dependent patch energies: two of the hydrophobic effect, and a more generic description. We conclude that while solubility inversion due to the hydrophobic effect may be possible, microscopic evidence to support it in $γ$D-crystallin is weak. More generally, we find that solubility inversion requires a fine balance between patch strengths and the temperature-dependent contribution, which may explain why inverted solubility is not commonly observed in proteins. In any event, we also find that the temperature-dependent interaction has only a negligible impact on the critical properties of the $γ$D-crystallin, in line with previous experimental observations.