The Onset of Molecule-Spanning Dynamics in Heat Shock Protein Hsp90

Protein dynamics have been investigated on a wide range of time scales. Nano- and picosecond dynamics have been assigned to local fluctuations, while slower dynamics have been attributed to larger conformational changes. However, it is largely unknown how fast (local) fluctuations can lead to slow global (allosteric) changes. Here, fast molecule-spanning dynamics on the 100 to 200 ns time scale in the heat shock protein 90 (Hsp90) are shown. Global real-space movements are assigned to dynamic modes on this time scale, which is possible by a combination of single-molecule fluorescence, quasi-elastic neutron scattering and all-atom molecular dynamics (MD) simulations. The time scale of these dynamic modes depends on the conformational state of the Hsp90 dimer. In addition, the dynamic modes are affected to various degrees by Sba1, a co-chaperone of Hsp90, depending on the location within Hsp90, which is in very good agreement with MD simulations. Altogether, this data is best described by fast molecule-spanning dynamics, which precede larger conformational changes in Hsp90 and might be the molecular basis for allostery. This integrative approach provides comprehensive insights into molecule-spanning dynamics on the nanosecond time scale for a multi-domain protein. Protein dynamics occur on a wide range of timescales and are key for protein functionality. An unprecedented combination of single-molecule fluorescence, quasi-elastic neutron scattering and all-atom molecular dynamics simulations reveals surprisingly fast molecule-spanning dynamics around 150 ns in the heat shock protein 90 (Hsp90). They depend on the conformational state of Hsp90 and are likely precursors for larger (allosteric) conformational changes.image