Racemic protein crystallography refers to the idea of crystallizing proteins from a racemic mixture of the natural, biologically-handed, molecule and its mirror image molecule (reviewed in Yeates and Kent, 2012). The latter must be chemically synthesized in the laboratory from D-amino acids while the natural molecule may be synthezised or expressed in a biological host by using traiditional molecular biology methods. Laura Zawadzke and Jeremy Berg were the first to execute the idea in 1993 using the small (45 amino acid) protein rubredoxin. An early motivation for pursuing such studies was the idea that structure determination might be easier or more robust using diffraction data from a centrosymmetric crystal, which requires growth from a racemic mixture. There are merits to this idea, and recent work has further explored the possibilities of certain advantages in phasing centrosymmetric protein diffraction data (Sawaya et al., 2012).

Setting aside possible advantages in phasing and structure determination that might arise with centrosymmetric protein crystals, there is now good reason to believe that racemic crystallography could have a much more profound impact, by dramatically improving the ease with which macromolecular crystals can be obtained; the crystallization problem remains the most serious and most vexing obstacle in macromolecular crystallography. The prediction in 1995 that crystallization from a racemic mixture might provide a critical advantage arose largely as a surprise while working on a mathematical explanation for why some special crystal space groups are preferred so strongly over others by proteins when they crystallize (i.e. in ordinary experiments involving only the natural biological hand). The preferences for different crystal space groups vary by more than two orders of magnitude, so understanding that phenomenon has potentially important implications for the crystallization problem as a whole. The paper by Stephanie Wukovitz in 1995 offered a mathematical explanation for the space group preference phenomenon; i.e. it explained why P212121 is by far the most commonly observed crystal space group for (ordinary chiral) proteins. Reaching farther, it was also noted at that time that the theory predicted that even more dominant crystal space groups existed among those that are only possible when using a racemic mixture. Two predictions were made: that proteins would crystallize with greater ease from racemic mixtures owing to the existence of especially favored racemic crystal symmetries, and that P1(bar) would be the dominant space group observed.

The invention of native chemical ligation methods by Phil Dawson and Stephen Kent in the early 1990’s opened up prospects for chemically synthesizing larger protein molecules. Kent and co-workers have since tested racemic crystallography on a wide range of protein molecules. Current data provide strong support for the idea that proteins do crystalize with realtive ease from synthetic racemic mixtures (and most often in P1(bar) as predicted).