Structural Systems Biology using Future Coherent Light Sources
Thomas Earnest
Physical Biosciences Division, Lawrence Berkeley National Laboratory
A full understanding of biology requires information about the atomic-resolution structures of biomolecules and their complexes, and the dynamic localization of biomolecular machines within the cell. The mapping of the functional interacteome from yeast has provided verification that most biomolecules exists in complexes within the cellular environment and have distinct subcellular localizations in prokaryotic and eukaryotic cells. Multi-protein complexes involved in numerous biological roles are sometimes dynamically relocalized during the cell cycle. Technologies and methods for structural biological research that allow scientists to probe and understand biology at atomic, molecular, and cellular resolutions, and over a biologically-relevant time scales are required. Furthermore the integration of the information from these experiments into the broad context of biological understanding requires the ability to perform experiments with high levels of scientific throughput.
The properties of the proposed Energy Recovery Linac at Cornell are particularly well matched to provide x-rays for research in structural systems biology. The ability to provide small x-ray beams with ultra-low divergence and high intensity will allow for the increased success in obtaining structures from crystals of large biomolecular complexes that frequently have large unit cell dimensions as well as small crystal sizes. Solution x-ray scattering experiments to determine the overall envelope of these complexes and structural changes that may occur upon interactions with other molecules will be able to be performed on very small volume samples at high-throughput. The advantages of the ERL for biological research are particularly important in the imaging of non-periodic samples such as cells to examine the subcellular localization of multi-protein complexes and organelles, and to follow their movement and interactions during the cell cycle. Diffractive imaging methods involving the sampling of the molecular transform of the object with coherent x-rays in three dimensions is an approach that has the capability of achieving resolution in the 5-10 nm range of unlabelled cells. The brightness and stability of the x-rays produced by the ERL provide a unique resource for these studies. Thus the dynamic interacteome of prokaryotic and eukaryotic cells can be elucidated by exploiting a number of methods for which the ERL will serve as an experimental resource of exceptionally high-quality coherent x-radiation. New instrumentation will need to be developed to take full advantage of the ERL's capabilities including advances in sample preparation, automation of sample exchange and data collection, and the development of a system of experimental control that will make biologists optimally productive.
