Summary
Biological function is almost uniquely exerted via interactions of biomacromolecules. Such interactions are still poorly understood and often involve large conformational changes, in extreme cases even from completely unfolded to folded structures. High resolution NMR has emerged as one of the most versatile tools for a precise description of biomolecules and their interactions, not only in terms of static structures, but also by kinetic, energetic, and thermodynamic parameters at the atomic level. It is the goal of this proposal to use and to develop the unique strengths of NMR to arrive at a more quantitative understanding of biomolecules and their interactions.
The proposal is divided into two subprojects:
Subproject A is directed towards the determination of structure, dynamics, and interactions in a number of protein systems where we have detailed biological information from in-house or external collaborations, but no or insufficient structural and dynamical data are available, and where solution NMR methods are expected to yield unique new information. Specifically, this subproject addresses protein-protein and protein-ligand interactions in cadherin-mediated cellular adhesion, antiobiotic resistance in Streptomyces, proteins of the Yersinia injectisome, the Bartonella type IV secretion system, and proteins involved in transcriptional elongation as well as nematocyst wall formation. In addition, we want to characterize the interactions of lipopolysaccharides (endotoxins) by novel NMR methods.
Subproject B is directed towards the development of novel NMR methods with a specific focus on the precise description of folding in model systems and of hydrogen bonds. In particular, it seems now possible to obtain a complete geometric description of the folding of peptides and small proteins in terms of angular distributions and order parameters from residual dipolar couplings. This could finally lead to a complete thermodynamic description of folding transitions in peptides and small proteins. We also want to continue our research on the spectroscopy of biomolecular hydrogen bonds with an emphasis on the influence of biomolecular dynamics on hydrogen bond parameters and a comparison between the thermodynamic behavior of protein and nucleic acid hydrogen bonds. The goal is to determine to what extent H-bonds contribute to the overall thermodynamic properties of biomolecules. Finally, we also want to start an exploratory project in solid state NMR of biomolecules with the goal to describe the influence of crystalline and non-crystalline environment on the line width of biomolecules in solid state NMR spectra.