De Novo Protein Modeling With X-ray Lasers

November 25, 2013 | Using the well-studied enzyme lysozyme as a proof-of-concept, researchers at Stanford's SLAC National Accelerator Laboratory have demonstrated that their Linac Coherent Light Source (LCLS) X-ray laser can generate 3D models of unknown proteins without any prior knowledge of their structure. The study, published yesterday in Nature, represents a major step forward in protein discovery, as X-ray lasers can capture details of proteins that do not form macroscopic crystals, previously the limiting factor in de novo protein modeling. LCLS has been used to fill in gaps in partially understood protein structures, but the technology has never before built a protein model from scratch. The process involved battering lysozyme microcrystals, treated with a gadolinoum solution, with X-ray pulses for femtoseconds at a time. X-ray diffraction was measured to build an electron density map that corresponded with the protein's 3D arrangement. The sheer volume of data generated during this battery required some novel analytical software to accurately interpret, ultimately resulting in a model that perfectly matched lysozyme's known structure. Now that the practice has been validated with lysozyme, it can be turned toward key biomolecules that have never been modeled, due to their inability to form the large crystals needed in traditional X-ray crystallography.