Using Schematic Models to Understand the Microscopic Basis for Inverted Solubility in γD-Crystallin

• Published in: The journal of physical chemistry. B 2019-11, Vol.123 (47), p.10061-10072
• Main Authors: Altan, Irem, Khan, Amir R, James, Susan, Quinn, Michelle K, McManus, Jennifer J, Charbonneau, Patrick
• Format: Article
• Language: English
• ISSN: 1520-6106; 1520-5207
• DOI: 10.1021/acs.jpcb.9b07774

Inverted solubilitymelting a crystal by coolingis observed in a handful of proteins, such as carbomonoxy hemoglobin C and γD-crystallin. In human γD-crystallin, the phenomenon is associated with the mutation of the 23rd residue, a proline, to a threonine, serine, or valine. One proposed microscopic mechanism entails an increase in surface hydrophobicity upon mutagenesis. Recent crystal structures of a double mutant that includes the P23T mutation allow for a more careful investigation of this proposal. Here, we first measure the surface hydrophobicity of various mutant structures of γD-crystallin and discern no notable increase in hydrophobicity upon mutating the 23rd residue. We then investigate the solubility inversion regime with a schematic patchy particle model that includes one of three variants of temperature-dependent patch energies: two of the hydrophobic effect, and one of a more generic nature. We conclude that, while solubility inversion due to the hydrophobic effect may be possible, microscopic evidence to support it in γD-crystallin is weak. More generally, we find that solubility inversion requires a fine balance between patch strengths and their temperature-dependent component, which may explain why inverted solubility is not commonly observed in proteins. We also find that the temperature-dependent interaction has only a negligible impact on liquid–liquid phase boundaries of γD-crystallin, in line with previous experimental observations.