Institute of Physical Chemistry, University of Freiburg, Albertstrasse 21, 79104, Freiburg, Germany.
Institute of Applied Physics, University of Tübingen, Auf der Morgenstelle 10, 72076, Tübingen, Germany.
Adv Sci (Weinh). 2023 Dec;10(36):e2304262. doi: 10.1002/advs.202304262. Epub 2023 Nov 20.
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.
蛋白质动力学的研究范围很广。纳秒和皮秒动力学被分配给局部波动，而较慢的动力学则归因于较大的构象变化。然而，目前还不清楚多快（局部）的波动可以导致较慢的全局（变构）变化。在这里，展示了热休克蛋白 90（Hsp90）中在 100 到 200 纳秒时间尺度上的快速分子跨越动力学。通过单分子荧光、准弹性中子散射和全原子分子动力学（MD）模拟的组合，将全局实空间运动分配到这个时间尺度上的动态模式。这些动态模式的时间尺度取决于 Hsp90 二聚体的构象状态。此外，Sba1（Hsp90 的共伴侣）的存在会以不同程度影响动态模式，这取决于 Hsp90 中的位置，这与 MD 模拟非常吻合。总的来说，这些数据最好通过快速的分子跨越动力学来描述，这种动力学发生在 Hsp90 较大构象变化之前，可能是变构的分子基础。这种综合方法为多域蛋白质的纳秒时间尺度上的分子跨越动力学提供了全面的见解。
