Liu Jie, Sankar Kannan, Wang Yuan, Jia Kejue, Jernigan Robert L
Bioinformatics and Computational Biology Interdepartmental Graduate Program, Iowa State University, Ames, Iowa; Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa.
Bioinformatics and Computational Biology Interdepartmental Graduate Program, Iowa State University, Ames, Iowa; Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa; Laurence H. Baker Center for Bioinformatics and Biological Statistics, Iowa State University, Ames, Iowa.
Biophys J. 2017 Apr 25;112(8):1561-1570. doi: 10.1016/j.bpj.2017.03.004.
Protein functional mechanisms usually require conformational changes, and often there are known structures for the different conformational states. However, usually neither the origin of the driving force nor the underlying pathways for these conformational transitions is known. Exothermic chemical reactions may be an important source of forces that drive conformational changes. Here we investigate this type of force originating from ATP hydrolysis in the chaperonin GroEL, by applying forces originating from the chemical reaction. Specifically, we apply directed forces to drive the GroEL conformational changes and learn that there is a highly specific direction for applied forces to drive the closed form to the open form. For this purpose, we utilize coarse-grained elastic network models. Principal component analysis on 38 GroEL experimental structures yields the most important motions, and these are used in structural interpolation for the construction of a coarse-grained free energy landscape. In addition, we investigate a more random application of forces with a Monte Carlo method and demonstrate pathways for the closed-open conformational transition in both directions by computing trajectories that are shown upon the free energy landscape. Initial root mean square deviation (RMSD) between the open and closed forms of the subunit is 14.7 Å and final forms from our simulations reach an average RMSD of 3.6 Å from the target forms, closely matching the level of resolution of the coarse-grained model.
蛋白质功能机制通常需要构象变化，并且不同构象状态往往有已知结构。然而，通常驱动这些构象转变的驱动力来源及其潜在途径均不为人所知。放热化学反应可能是驱动构象变化的重要力源。在此，我们通过应用化学反应产生的力来研究伴侣蛋白GroEL中源自ATP水解的这类力。具体而言，我们施加定向力来驱动GroEL的构象变化，并了解到施加的力存在一个高度特定的方向，可驱动其从封闭形式转变为开放形式。为此，我们利用粗粒度弹性网络模型。对38个GroEL实验结构进行主成分分析得出最重要的运动，这些运动用于结构插值以构建粗粒度自由能景观。此外，我们用蒙特卡罗方法研究更随机的力的应用，并通过计算在自由能景观上显示的轨迹来展示封闭 - 开放构象转变在两个方向上的途径。亚基开放和封闭形式之间的初始均方根偏差（RMSD）为14.7 Å，我们模拟得到的最终形式与目标形式的平均RMSD达到3.6 Å，与粗粒度模型的分辨率水平紧密匹配。
