System-Level Simulation of a Bioenergetic Membrane

 描述（由申请人提供）：生物能量膜是一种关键的细胞装置，它执行一系列相互关联的能量转换过程，为细胞提供ATP和关键代谢物。单个过程和它们的膜蛋白已经被深入研究，但很少有过程一起研究，特别是不是在一个完整的细胞器的规模。其原因是缺乏全膜原子分辨率模型和巨大的复杂性。在一个相当原始但仍然具有代表性的生物能膜的情况下，即紫色细菌的光合色素细胞，其整体结构最近已经在原子细节中描述，也是巨大的，原子数为1亿;然而，今天可以使用计算工具和计算机能力来研究整个系统。该提案寻求资金，以研究色素细胞的几个步骤：（1）建立一个1亿个原子的整个色素细胞模型，并通过分子动力学模拟，以描述其关键的物理性质，如醌/醌在脂质相中的扩散，以及整体氧化还原状态依赖的静电。(2)从这个详细的模拟获得的结构洞察力指导随后的多尺度模拟的膜宽的电荷传输通过蛋白质（细胞色素c2）和脂质（醌/醌醇）的扩散和结合。(3)通过核糖体连接的插入酶YidC和ATP合酶中的定子和转子结构域之间的耦合的关键生物能量蛋白插入到膜中的动力学通过分子动力学描述。这项研究将为未来生物能量和其他细胞器的全膜研究奠定基础。

 DESCRIPTION (provided by applicant): Bioenergetic membranes are a key cellular apparatus that carry out a series of interlinked energy conversion processes providing ATP and key metabolites for a cell. The individual processes and their underlying membrane proteins have been investigated intensively, but rarely have the processes been studied together, in particular not on the scale of a full organelle. The reasons are both lack of whole-membrane atomic resolution models and huge complexity. In case of a rather primitive, yet still representative bioenergetic membrane, namely the photosynthetic chromatophore of purple bacteria, the overall structure has been recently described in atomic detail, also huge with an atom count of 100 million; however, computational tools and computer power are available today to investigate the system as a whole. This proposal seeks funds to study the chromatophore in several steps: (1) A 100 million atom model of an entire chromatophore is built and simulated through molecular dynamics to describe its key physical properties, such as quinol/quinone diffusion in the lipid phase as well as overall redox-state-dependent electrostatics. (2) Structural insight gained from this detailed simulation guides subsequent multiscale simulations of the membrane-wide charge transport via protein (cytochrome c2) and lipid (quinone/quinol) diffusion and binding. (3) Dynamics of insertion of key bioenergetic proteins into the membrane through the ribosome-linked insertase YidC and the coupling between the stator and rotor domains in ATP synthase are described through molecular dynamics. The proposed study will provide the groundwork for future membrane-wide investigations of bioenergetic and other cellular organelles.