NMR for Structural Proteomics: creating a high-throughput environment
Martin Billeter, Biophysics Group, Department of Chemistry

Structural Proteomics aims at the determination of a three-dimensional protein structure for each gene product. A survey of the most successful consortia in this field reveals that NMR can provide a share of up to 50%. The high-throughput level necessary in such efforts requires efficient tools at all levels: recording of spectra, processing of these, resonance assignment (the most critical step in structural NMR) and structure calculation. During the past years we have been developing, testing and applying high-throughput NMR tools covering all steps except structure calculation. These tools include: (1) protocols and algorithms (with implementation) for optimized recording of so called "sparse" NMR data, saving about 75% of NMR instrument time; (2) algorithms and programs for the interpretation of NMR spectra using decomposition and signal identification, providing reliable input for the assignment and structure calculation; (3) automated resonance assignment tools, reducing the NMR approach from weeks of interactive work to hours of computer calculations. In this context, the major goal for the next years is to establish and apply an efficient, versatile, reliable and easy-to-use procedure for high-throughput NMR in Structural Proteomics. This procedure encompasses recording and processing of sparse (and other) NMR data, reliable signal identification in the resulting NMR spectra, and automated resonance assignment. The main targets are spectra on novel proteins resulting from ongoing Structural Proteomics projects. The procedure will take advantage of our own developments, for example three-way decomposition or algorithms for peak picking and resonance assignments, as well as those of our collaboration partners, for example reduced dimensionality as used in projection spectroscopy ("GFT approach"). A second goal is the application of the above tools for related problems such as optimized analysis of NMR data obtained in drug discovery or characterization of protein dynamics (using NMR relaxation data). The available infrastructure includes access to well-equipped high-field instruments at the Swedish NMR Centre (500-900 MHz spectrometers). The project addresses problems at the interface of several scientific fields: biophysics (NMR), computer and mathematics (signal analysis, optimization), biology (protein folding and function). For this project, a degree in physics, biophysics or physical chemistry would provide a good starting point; students with a more biological background (e.g. from biochemistry) could supplement their education in the initial PhD phase with courses in physics (spectroscopy, thermodynamics). Knowledge of computer systems (Linux, some programming language) is central.