The Computational Microscope

细胞是生命的基石，但它们本身也是蛋白质、小分子和溶剂的集合体，当孤立地看待它们时，它们中的任何一个都不会被认为是活的。生物是如何从分子的“行为”中产生的，分子只是服从物理定律，这是现代生物学的基本难题。科学超级计算的兴起提供了在原子、细胞以及其间所有层次上研究生命系统的机会。 现在，在千万亿次计算的时代，有了像Blue沃茨这样的计算资源，通过描述由数十亿个原子组成的数千个大分子的组装和合作，从无生命物质到有生命物质的最关键一步正在成为可能。本提案中的项目将使用Blue沃茨来研究马达蛋白的化学机械性质，以及对细菌趋化性和植物纤维代谢起中心作用的大分子复合物的结构和功能。值得注意的是，所有项目都建立在以前广泛的工作基础上。第一个项目将研究两个运动系统的机制：ClpX解折叠酶的蛋白质解折叠和细胞质动力蛋白的细胞骨架货物运输。化学传感器阵列项目旨在回答来自细菌表面上许多化学传感器的输入如何在阵列中的数百纳米范围内进行转导，从而导致细胞决定是否应该继续游泳或改变方向，以适应不断变化的环境。多纤维素体项目旨在回答为什么与其他细菌产生的多纤维素体相比，人类肠道细菌产生如此复杂的多纤维素体。 所有项目将利用计算方法来结合联合收割机来自不同分辨率的多个来源的结构数据（单个蛋白质的X射线晶体学，多蛋白质系统的中分辨率cryo-EM，以及亚细胞器的低分辨率cryo-EM断层扫描），产生尺寸为100 nm的结构的原子分辨率结构模型，包含1000 -100百万个原子。该项目的更广泛影响是正在开发非常受欢迎的NAMD和VMD软件（注册用户超过30万），该软件与PI的长期培训工作相结合，将使世界各地的研究人员能够解决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.