Protein crystallization in drug design: towards a rational approach

X-ray crystallography is the method of choice for the detailed characterization of stereochemistry of interactions of drug leads and potential chemotherapeutics with their protein targets. The resulting atomic models allow for rational enhancement of the lead properties and consequently for the design of high-affinity inhibitors. However, a major bottleneck of the technique is the requirement for the protein and its complexes to yield high quality single crystals. Furthermore, it is highly desirable that such crystals diffract to high resolution, preferably ≥ 1.2 Å, revealing the structures in atomic detail. Unfortunately, only a small portion of proteins readily crystallize in that fashion. New approaches are being developed to circumvent this problem. One proposed option includes rational protein surface engineering to systematically improve the crystallizability of the protein. This is accomplished by creating surface patches readily mediating weak, but specific, intermolecular interactions that take on the role of crystal contacts during nucleation and crystal growth phase.