  Protein crystal production is a major bottleneck for the structural
characterisation 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
optimising crystallization. The relative scarcity of sophisticated theoretical
models that include sufficient detail to link collective behaviour, captured in
protein phase diagrams, and molecular level details, determined from
high-resolution structural information is a further barrier. Here we present
two crystals structures for the P23TR36S mutant of gamma D-crystallin, each
with opposite solubility behaviour, 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 stabilise 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 an
alternative strategy for the rationalization of protein crystallization.
