Paddling mechanism for the substrate translocation by AAA plus motor revealed by multiscale molecular simulations
Paddling mechanism for the substrate translocation by AAA plus motor revealed by multiscale molecular simulations
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DOI：
10.1073/pnas.0904756106
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发表时间：
2009-10-27
影响因子：
11.1
通讯作者：
Takada, Shoji
中科院分区：
文献类型：
--
作者：
Koga, Nobuyasu;Kameda, Tomoshi;Takada, Shoji
六聚环状AAA+分子马达具有使大分子链通过中心孔主动移位的关键功能。通过进行多尺度分子动力学（MD）模拟，我们揭示了HslU，一个AAA+马达在细菌同源的真核蛋白酶体，通过划桨机制在ATP驱动的循环构象变化的底物多肽易位。首先，全原子MD模拟显示HslU孔通过高度保守的Tyr-91和瓦尔-92以HslU的封闭形式牢固地和以开放形式松散地抓住螺纹信号肽。抓地力取决于基板序列。这些功能被送入粗粒度的MD，和构象转变的HslU ATP循环进行了模拟。模拟显示多肽的随机单向易位。这种单向移位归因于Tyr-91在开放和封闭状态之间的划动运动：Tyr-91抓着基底向下运动，在基底上向上滑动，划动运动是由Tyr-91的孔半径变化和上下位移的特征时间尺度的差异引起的。对孔和基片突变的计算实验与几个实验结果雅阁。
Hexameric ring-shaped AAA+ molecular motors have a key function of active translocation of a macromolecular chain through the central pore. By performing multiscale molecular dynamics (MD) simulations, we revealed that HslU, a AAA+ motor in a bacterial homologue of eukaryotic proteasome, translocates its substrate polypeptide via paddling mechanism during ATP-driven cyclic conformational changes. First, fully atomistic MD simulations showed that the HslU pore grips the threaded signal peptide by the highly conserved Tyr-91 and Val-92 firmly in the closed form and loosely in the open form of the HslU. The grip depended on the substrate sequence. These features were fed into a coarse-grained MD, and conformational transitions of HslU upon ATP cycles were simulated. The simulations exhibited stochastic unidirectional translocation of a polypeptide. This unidirectional translocation is attributed to paddling motions of Tyr-91s between the open and the closed forms: downward motions of Tyr-91s with gripping the substrate and upward motions with slipping on it. The paddling motions were caused by the difference between the characteristic time scales of the pore-radius change and the up-down displacements of Tyr-91s. Computational experiments on mutations at the pore and the substrate were in accord with several experiments.