Objective NMR spectroscopy detects in a unique way with atomic resolution biomolecular dynamics in the previously hidden time range between approximately 5 nano- to 50 microseconds (ns-ms time range). The detection of this motion happens in equilibrium under physiological conditions without the need for a triggering reaction. On the example of ubiquitin, this dynamics was found by us to be important for molecular recognition between proteins implying conformational selection rather than induced fit. Only free solution ensembles including this dynamics accessed the full conformational heterogeneity of structures in recognition complexes. Molecular dynamics analysis suggests high correlation of these ns-ms dynamical modes. Here, we propose to establish with NMR experimentally the correlated nature of the ns-ms dynamics, to describe ensembles reflecting ns-ms and sub-ns dynamics by separating the time scales. In this context, using temperature jump-infra-red spectroscopy and solid state NMR we want to determine the time scale of the ns to ms motion more precisely. Since the ns-ms time scale is slower than diffusion, dynamics on this time scale could be a mechanism of regulating or limiting the kinetics of molecular association and recognition. Therefore, we want to determine on-rates by NMR spectroscopy and want to explore whether mutants that do not affect the binding interface but will affect the dynamics modulate the on-rates. This would allow the control of binding kinetics and explore the influence of ns-¼s dynamics on protein-protein recognition on the long run also for membrane proteins. In addition specificity for drug interactions could be increased addressing extremal conformations present in the ns-¼s ensembles for homologous proteins with otherwise very similar average structures at interaction interfaces. If the proposal is successful this would open up new opportunities for drug design and design of protein-protein interactions. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsmedical and health sciencesbasic medicinemedicinal chemistrynatural sciencesphysical sciencesopticsspectroscopyabsorption spectroscopy Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-AG-LS1 - ERC Advanced Grant - Molecular and Structural Biology and Biochemistry Call for proposal ERC-2008-AdG See other projects for this call Funding Scheme ERC-AG - ERC Advanced Grant Coordinator MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Address Hofgartenstrasse 8 80539 Munchen Germany See on map Region Bayern Oberbayern München, Kreisfreie Stadt Activity type Research Organisations Administrative Contact Manfred Messerschmidt (Mr.) Principal investigator Christian Griesinger (Prof.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution € 2 212 000,00 Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Germany EU contribution € 2 212 000,00 Address Hofgartenstrasse 8 80539 Munchen See on map Region Bayern Oberbayern München, Kreisfreie Stadt Activity type Research Organisations Administrative Contact Manfred Messerschmidt (Mr.) Principal investigator Christian Griesinger (Prof.) Links Contact the organisation Opens in new window Website Opens in new window
