Temperature-Dependent Interactions Explain Normal and Inverted Solubility in a γD-Crystallin Mutant

Amir R. Khan, Susan James, Michelle K. Quinn, Irem Altan, Patrick Charbonneau, Jennifer J. McManus*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

2 Citations (Scopus)


Protein crystal production is a major bottleneck in the structural characterization of proteins. To advance beyond large-scale screening, rational strategies for protein crystallization are crucial. Understanding how chemical anisotropy (or patchiness) of the protein surface, due to the variety of amino-acid side chains in contact with solvent, contributes to protein-protein contact formation in the crystal lattice is a major obstacle to predicting and optimizing crystallization. The relative scarcity of sophisticated theoretical models that include sufficient detail to link collective behavior, captured in protein phase diagrams, and molecular-level details, determined from high-resolution structural information, is a further barrier. Here, we present two crystal structures for the P23T + R36S mutant of γD-crystallin, each with opposite solubility behavior: one melts when heated, the other when cooled. When combined with the protein phase diagram and a tailored patchy particle model, we show that a single temperature-dependent interaction is sufficient to stabilize the inverted solubility crystal. This contact, at the P23T substitution site, relates to a genetic cataract and reveals at a molecular level the origin of the lowered and retrograde solubility of the protein. Our results show that the approach employed here may present a productive strategy for the rationalization of protein crystallization.

Original languageEnglish
Pages (from-to)930-937
Number of pages8
JournalBiophysical Journal
Issue number5
Publication statusPublished - 3 Sep 2019


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