Computational Science Program, The University of Texas at El Paso, El Paso, TX 79912, USA.
Department of Physics, The University of Texas at El Paso, El Paso, TX 79912, USA.
Int J Mol Sci. 2022 Feb 12;23(4):2035. doi: 10.3390/ijms23042035.
Cargo transport within cells is essential to healthy cells, which requires microtubules-based motors, including kinesin. The C-terminal tails (E-hooks) of alpha and beta tubulins of microtubules have been proven to play important roles in interactions between the kinesins and tubulins. Here, we implemented multi-scale computational methods in E-hook-related analyses, including flexibility investigations of E-hooks, binding force calculations at binding interfaces between kinesin and tubulins, electrostatic potential calculations on the surface of kinesin and tubulins. Our results show that E-hooks have several functions during the binding process: E-hooks utilize their own high flexibilities to increase the chances of reaching a kinesin; E-hooks help tubulins to be more attractive to kinesin. Besides, we also observed the differences between alpha and beta tubulins: beta tubulin shows a higher flexibility than alpha tubulin; beta tubulin generates stronger attractive forces (about twice the strengths) to kinesin at different distances, no matter with E-hooks in the structure or not. Those facts may indicate that compared to alpha tubulin, beta tubulin contributes more to attracting and catching a kinesin to microtubule. Overall, this work sheds the light on microtubule studies, which will also benefit the treatments of neurodegenerative diseases, cancer treatments, and preventions in the future.
细胞内的货物运输对健康细胞至关重要，这需要基于微管的马达，包括驱动蛋白。微管的α和β微管蛋白的 C 端尾部（E 钩）已被证明在驱动蛋白和微管蛋白之间的相互作用中发挥重要作用。在这里，我们在 E 钩相关分析中实施了多尺度计算方法，包括 E 钩的柔性研究、驱动蛋白和微管蛋白结合界面的结合力计算、驱动蛋白和微管蛋白表面的静电势能计算。我们的结果表明，E 钩在结合过程中有几个功能：E 钩利用其自身的高柔性来增加与驱动蛋白接触的机会；E 钩有助于微管蛋白对驱动蛋白更具吸引力。此外，我们还观察到α和β微管蛋白之间的差异：β微管蛋白比α微管蛋白具有更高的灵活性；β微管蛋白在不同距离处产生更强的吸引力（约两倍的强度）到驱动蛋白，无论结构中是否有 E 钩。这些事实可能表明，与α微管蛋白相比，β微管蛋白对吸引和捕获驱动蛋白到微管的贡献更大。总的来说，这项工作为微管研究提供了新的思路，这也将有助于未来神经退行性疾病、癌症治疗和预防的治疗。
