Progress in the Development of an Alternative Approach to Macromolecular Crystallization

We are developing an alternate strategy for the crystallization of macromolecules that does not, like current methods, depend on the optimization of traditional variables such as pH and precipitant concentration, but is based on the hypothesis that many conventional small molecules might establish stabilizing, intermolecular, noncovalent cross-links in crystals, and thereby promote lattice formation. Earlier experiments provided encouraging results that suggested further research was warranted (Larson, S. B.; Day, J. S.; Cudney, R.; McPherson, A. A novel strategy for the crystallization of proteins: X-ray diffraction validation. Acta Crystallogr., D: Biol. Crystallogr. 2007, 63, 310−318. McPherson, A.; Cudney, B. Searching for silver bullets: an alternative strategy for crystallizing macromolecules. J. Struct. Biol. 2006, 156, 387−406). Here we report additional, large-scale crystallization screening experiments that lend further support, though they suggest that additional mechanisms may play a positive ...