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Content archived on 2024-06-18

NMR detected nanosecond to microsecond dynamics for biomolecular recognition dynamics

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.

Call for proposal

ERC-2008-AdG
See other projects for this call

Host institution

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
EU contribution
€ 2 212 000,00
Address
HOFGARTENSTRASSE 8
80539 Munchen
Germany

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Region
Bayern Oberbayern München, Kreisfreie Stadt
Activity type
Research Organisations
Administrative Contact
Manfred Messerschmidt (Mr.)
Principal investigator
Christian Griesinger (Prof.)
Links
Total cost
No data

Beneficiaries (1)