System-Level Simulation of a Bioenergetic Membrane

 描述(申请人提供)：生物能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。人们对各个过程及其下层膜蛋白进行了深入的研究，但很少有人将这些过程放在一起研究，特别是在完整细胞器的规模上。究其原因，既有全膜原子分辨率模型的缺乏，又有巨大的复杂性。在一个相当原始但仍然具有代表性的生物能量膜的情况下，即紫色细菌的光合色团，总体结构最近被原子细节描述，也是巨大的，原子计数为1亿；然而，今天可以用计算工具和计算机能力来研究整个系统。(1)建立了一个完整的生色团的1亿原子模型，并通过分子动力学对其进行了模拟，以描述其关键的物理性质，如在脂相中的苯酚/苯醌扩散以及整个氧化还原态相关的静电学。(2)从这个详细的模拟中获得的结构洞察力指导了随后的多尺度模拟通过蛋白质(细胞色素c2)和脂类(苯醌/喹酚)的扩散和结合来进行膜范围的电荷传输。(3)用分子动力学方法描述了关键生物高能蛋白通过核糖体连接插入酶YidC插入细胞膜的动力学，以及ATP合成酶定子和转子结构域之间的耦合。这项拟议的研究将为未来生物能量学和其他细胞器的膜范围研究提供基础。

 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.