Research
Interests
NMR-based Computational Structural Biology
Computation methods to study biomolecular systems, in particular by nuclear magnetic resonance (NMR), are the focus of our research. The relationship between structure, dynamics and function of biological macromolecules is of fundamental importance for understanding life at a molecular level, and a key element of rational drug design. The three-dimensional structure has a piv¬otal role, since its knowledge is essential to understand the physical, chemical, and bi¬ological properties of a protein. Until recently NMR protein structure determination was a laborious undertaking that occupied a trained spectroscopist for months or years for each new protein structure. This situation has changed by the introduction of automated, computational systems. We are extending NMR protein structure analysis to hitherto inaccessible systems, including proteins larger than 40 kDa, membrane proteins, and proteins studied directly inside living cells.
- Protein structure analysis
Three-dimensional structures of proteins in solution can be calculated on the basis of conformational restraints derived from NMR measurements. Our CYANA program package, based on simulated annealing by molecular dynamics simulation in torsion angle space and the automated assignment of NOE distance restraints, is one of the most widely used algorithms for this purpose. Automated methods for protein structure determination by NMR have increasingly gained acceptance and are now widely used for the automated assignment of distance restraints and the calculation of three-dimensional structures. Our FLYA algorithm for the fully automated NMR structure determination of proteins is suitable to substitute all manual spectra analysis and thus overcomes a major efficiency limitation of the NMR method for protein structure determination. Fully automated structure determination of proteins in solution (FLYA) yields, without human intervention, three-dimensional protein structures starting from a set of multidimensional NMR spectra. As in the classical manual approach, structures are determined by a set of experimental NOE distance restraints without reference to already existing structures or empirical molecular modeling information. In addition to the three-dimensional structure of the protein, FLYA yields backbone and side-chain chemical shift assignments, and cross peak assignments for all spectra. - two
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