Schneider (Thomas) Group
Tools for structure determination and analysis
Rigid regions (centre; blue and green) identified from ensembles of structures can be used for superposition and subsequent analysis (left) or as fragments to interpret experimental data from methods with lower resolution than X-ray crystallography (right).
Previous and current research
The group pursues two major activities: 1) the construction of three beamlines for structural biology at the new PETRA III synchrotron in Hamburg; and 2) the development of computational methods to extract the information from structural data.
The three beamlines we are constructing will harness the extremely brilliant beam of the PETRA III synchrotron for small angle X-ray scattering on solutions and X-ray crystallography on crystals of biological macromolecules.The beamlines will be embedded in an integrated facility for structural biology. This facility will support non-specialists not only in performing the actual experiments with synchrotron radiation, but also in sample preparation and the evaluation of the measured data. The construction of the beamlines is done in close collaboration with Stefan Fiedler’s team.
Partly due to the enormous progress in synchrotron radiation-based structural biology, structural data on biological macromolecules are produced at an ever-increasing rate, creating the need to develop tools for efficient mining of structural data. We are developing tools for which the central concept is to use coordinate errors throughout all calculations. The necessity of this approach becomes clear when one considers that in the contrast to sequence data, where a nucleotide entry can only be right or wrong, the precision in the location of an atom in a crystal structure can vary over several orders of magnitude. While the position of an atom in a rigid region of a protein giving diffraction data to high resolution may be known to within 0.01 Å, for an atom in a flexible region of a poorly diffracting protein, the coordinate error may reach more than 1.0 Å.
From a technical point of view, extracting information from large amounts of raw structural data (up to as many as hundreds of structures containing thousands of atoms each) is a very complex task and requires sophisticated algorithms both for the analysis and for the presentation and 3D visualisation of the results. During the last few years, we have been implementing various algorithms in a framework for the analysis of different conformations of the same molecule. Presently, we are expanding the scope of the methods to investigate homologous structures.
Future projects and goals
For the integrated facility for structural biology, our goal is to provide beamlines that are ready for user experiments by 2011. In small-angle X-ray scattering, the new beamlines will enable us to work with more complex and more dilute samples than presently possible. In macromolecular crystallography, the beamlines will provide features such as micro-focusing and energy tunability, allowing imaging of the content of small crystals containing large objects such as multi-component complexes.
On the computational side, we will work on improving the error models underlying our methods and on expanding our computational framework using genetic and graph based algorithms. We also plan to use recurrent structural fragments extracted from ensembles of structures as search models in molecular replacement and for the interpretation of low-resolution electron density maps. In fact, this aspect of our computational work will be very helpful in the interpretation of diffraction experiments on weakly diffracting large systems on the future PETRA III beamlines.