School of Grain Science and Technology, Jiangsu University of Science and Technology, Zhenjiang 212100, People's Republic of China.
Jiangsu Provincial Engineering Research Center of Grain Bioprocessing, Zhenjiang 212100, People's Republic of China.
Langmuir. 2024 Aug 6;40(31):16454-16462. doi: 10.1021/acs.langmuir.4c01776. Epub 2024 Jul 24.
The significant inconsistency between the experimental and simulation results of the free energy for the translocon-assisted insertion of the transmembrane helix (TMH) has not been reasonably explained. Understanding the mechanism of TMH insertion through the translocon is the key to solving this problem. In this study, we performed a series of coarse-grained molecular dynamics simulations and calculated the potential mean forces (PMFs) for three insertion processes of a hydrophobic TMH. The simulations reveal the pathway of the TMH insertion assisted by a translocon. The results indicate that the TMH contacts the top of the lateral gate first and then inserts down the lateral gate, which agrees with the sliding model. The TMH begins to transfer laterally to the bilayer when it is blocked by the plug and reaches the exit of the lateral gate, where there is a free energy minimum point. We also found that the connecting section between TM2 and TM3 of Sec61α prevented TMH from leaving the lateral gate and directly transitioning to the surface-bound state. These findings provide insight into the mechanism of the insertion of TMH through the translocon.
跨膜螺旋（TMH）在易位子协助下插入的自由能的实验和模拟结果之间存在显著差异，这一差异尚未得到合理的解释。理解跨膜易位子协助下的 TMH 插入机制是解决这一问题的关键。在本研究中，我们进行了一系列粗粒化分子动力学模拟，并计算了三个疏水 TMH 插入过程的势平均力（PMF）。模拟揭示了跨膜易位子协助下 TMH 插入的途径。结果表明，TMH 首先与侧向门的顶部接触，然后向下插入侧向门，这与滑动模型一致。当 TMH 被塞子阻塞并到达侧向门的出口时，它开始向双层横向转移，此时存在一个自由能最低点。我们还发现 Sec61α 的 TM2 和 TM3 之间的连接段阻止 TMH 离开侧向门并直接过渡到表面结合状态。这些发现为 TMH 通过跨膜易位子的插入机制提供了深入的了解。
