Shaikh Saher, Wen Po-Chao, Enkavi Giray, Huang Zhijian, Tajkhorshid Emad
Department of Biochemistry, Beckman Institute, and Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, U.S.A.
J Comput Theor Nanosci. 2010 Dec;7(12):2481-2500. doi: 10.1166/jctn.2010.1636.
Conformational changes of proteins are involved in all aspects of protein function in biology. Almost all classes of proteins respond to changes in their environment, ligand binding, and interaction with other proteins and regulatory agents through undergoing conformational changes of various degrees and magnitudes. Membrane channels and transporters are the major classes of proteins that are responsible for mediating efficient and selective transport of materials across the cellular membrane. Similar to other proteins, they take advantage of conformational changes to make transitions between various functional states. In channels, large-scale conformational changes are mostly involved in the process of "gating", i.e., opening and closing of the pore of the channel protein in response to various signals. In transporters, conformational changes constitute various steps of the conduction process, and, thus, are more closely integrated in the transport process. Owing to significant progress in developing highly efficient parallel algorithms in molecular dynamics simulations and increased computational resources, and combined with the availability of high-resolution, atomic structures of membrane proteins, we are in an unprecedented position to use computer simulation and modeling methodologies to investigate the mechanism of function of membrane channels and transporters. While the entire transport cycle is still out of reach of current methodologies, many steps involved in the function of transport proteins have been characterized with molecular dynamics simulations. Here, we present several examples of such studies from our laboratory, in which functionally relevant conformational changes of membrane channels and transporters have been characterized using extended simulations.
蛋白质的构象变化涉及生物学中蛋白质功能的各个方面。几乎所有种类的蛋白质都会通过经历不同程度和幅度的构象变化来响应其环境变化、配体结合以及与其他蛋白质和调节因子的相互作用。膜通道和转运蛋白是负责介导物质有效且选择性地跨细胞膜运输的主要蛋白质类别。与其他蛋白质类似，它们利用构象变化在不同功能状态之间进行转换。在通道中，大规模的构象变化主要参与“门控”过程，即通道蛋白的孔响应各种信号而打开和关闭。在转运蛋白中，构象变化构成了传导过程的各个步骤，因此在运输过程中整合得更为紧密。由于分子动力学模拟中高效并行算法的显著进展以及计算资源的增加，再加上膜蛋白高分辨率原子结构的可得性，我们处于前所未有的有利位置，可以使用计算机模拟和建模方法来研究膜通道和转运蛋白的功能机制。虽然目前的方法仍无法触及整个运输循环，但运输蛋白功能中涉及的许多步骤已通过分子动力学模拟得以表征。在此，我们展示来自我们实验室的此类研究的几个例子，其中使用扩展模拟对膜通道和转运蛋白功能相关的构象变化进行了表征。
