The Computational Microscope

细胞是生命的基石，但它们本身是蛋白质、小分子和溶剂的集合，当分离出来时，这些都不会被认为是活的。生物如何从分子的“行为”中产生，这是现代生物学的基本难题。分子的“行为”完全符合物理定律。科学超级计算的兴起为研究原子、细胞以及介于两者之间的所有层次的生命系统提供了机会。现在，在千万亿级计算的时代，有了像Blue Waters这样的计算资源，通过描述由数十亿个原子组成的数千个大分子的组装和协作，可以迈出从无生命到有生命的最关键的一步。这项计划中的项目将使用Blue Waters来研究马达蛋白质的化学机械性质，以及细菌趋化和植物纤维新陈代谢的核心大分子复合体的结构和功能。值得注意的是，所有项目都建立在大量以前工作的基础上。第一个项目将研究两个运动系统的机制：由ClpX解折叠酶解开的蛋白质和由胞浆动力蛋白运输的细胞骨架货物。化学传感阵列项目试图回答细菌表面许多化学传感器的输入是如何在阵列中的数百纳米范围内传递的，从而使细胞决定是应该继续游泳还是改变方向，以适应不断变化的环境。纤维素体项目旨在回答为什么与其他细菌产生的纤维素体相比，人类肠道细菌产生如此精细的纤维素体。所有这些项目都将利用计算方法将来自不同分辨率的多个来源的结构数据(单个蛋白质的X射线结晶学、多蛋白质系统的中分辨率冷冻EM，以及亚细胞细胞器的低分辨率冷冻EM断层扫描)结合在一起，产生尺寸约为100纳米、包含1000-1亿个原子的结构的原子分辨率结构模型。该项目的更广泛影响是正在开发广受欢迎(超过300,000注册用户)的NAMD和VMD软件，与PI的长期培训努力相结合，将使世界各地的研究人员能够满足人类的关键健康和能源需求。

Cells are the building blocks of life, yet they are themselves a collection of proteins, small molecules, and solvent, none of which, when taken in isolation, would be considered alive. How living things can arise from the "behavior" of molecules, which are simply obeying the laws of physics, is the essential conundrum of modern biology. The rise of scientific supercomputing has offered the chance to study living systems at the level of atoms, cells, and all levels in between. Now, in the era of petascale computing, with computational resources like Blue Waters, it is becoming possible to take the most critical step from inanimate to animate matter by describing assembly and cooperation of thousands of macromolecules made of billions of atoms.The projects in this proposal will use Blue Waters to study the chemo-mechanical properties of motor proteins, and the structure and function of the macromolecular complexes central to bacterial chemotaxis and plant fiber metabolism. Notably, all the projects build on extensive previous work. The first project will study the mechanisms of two motor systems: protein unfolding by ClpX unfoldase and cytoskeletal cargo transport by cytoplasmic dynein. The chemosensory array project seeks to answer how input from many chemical sensors on the bacterial surface are transduced across hundreds of nanometers in the array, leading the cell to decide if it should continue swimming or change direction, to adapt to changing environments. The cellulosome project aims to answer why human gut bacteria produces such an elaborate cellulosome when compared to the cellulosomes produced by other bacteria. All the projects will leverage computational methods to combine structural data from multiple sources of differing resolutions (X-ray crystallography of individual proteins, medium-resolution cryo-EM of multi-protein systems, and low-resolution cryo-EM tomography of subcellular organelles) yielding atomic-resolution structural models of structures on the order of 100 nm in size, containing 10-100 million atoms. The broader impacts of the project is the ongoing development of the hugely popular (over 300,000 registered users) NAMD and VMD software, which, combined with the longstanding training efforts of the PIs, will enable researchers worldwide to address key health and energy needs of mankind.