Molecular Biomechanics, Heidelberger Institut für Theoretische Studien gGmbH, Heidelberg, Germany.
Biophys J. 2012 Nov 21;103(10):2195-202. doi: 10.1016/j.bpj.2012.09.008. Epub 2012 Nov 20.
Heat-shock protein 90 (Hsp90) is an ubiquitous chaperone that is essential for cell function in that it promotes client-protein folding and stabilization. Its function is tightly controlled by an ATP-dependent large conformational transition between the open and closed states of the Hsp90 dimer. The underlying allosteric pathway has remained largely unknown, but it is revealed here in atomistic detail for the Escherichia coli homolog HtpG. Using force-distribution analysis based on molecular-dynamics simulations (>1 μs in total), we identify an internal signaling pathway that spans from the nucleotide-binding site to an ~2.3-nm-distant region in the HtpG middle domain, that serves as a dynamic hinge region, and to a putative client-protein-binding site in the middle domain. The force transmission is triggered by ATP capturing a magnesium ion and thereby rotating and bending a proximal long α-helix, which represents the major force channel into the middle domain. This allosteric mechanism is, with statistical significance, distinct from the dynamics in the ADP and apo states. Tracking the distribution of forces is likely to be a promising tool for understanding and guiding experiments of complex allosteric proteins in general.
热休克蛋白 90（Hsp90）是一种普遍存在的伴侣蛋白，对于细胞功能至关重要，因为它促进了客户蛋白的折叠和稳定。其功能受到 Hsp90 二聚体开放和关闭状态之间的 ATP 依赖性大构象转变的严格控制。尽管潜在的变构途径在很大程度上仍然未知，但在这里以原子细节揭示了大肠杆菌同源物 HtpG 的变构途径。使用基于分子动力学模拟的力分布分析（总计>1 μs），我们确定了一条从核苷酸结合位点到 HtpG 中间结构域中约 2.3nm 远的区域的内部信号通路，该区域充当动态铰链区域，并到中间结构域中的假定客户蛋白结合位点。力传递是由 ATP 捕获镁离子触发的，从而旋转和弯曲近端长α-螺旋，这是进入中间结构域的主要力通道。这种变构机制与 ADP 和无配体状态的动力学有统计学意义上的区别。跟踪力的分布可能是理解和指导一般复杂变构蛋白实验的有前途的工具。
