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，如果单独来看，没有一种是有生命的。生物是如何从分子的“行为”中产生的，分子只是遵循物理定律，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、细胞以及两者之间的所有水平上研究生命系统的机会。现在，在千万亿次计算的时代，有了像蓝水这样的计算资源，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，从无生命的物质到有生命的物质，迈出最关键的一步成为可能。本项目将利用Blue Waters研究运动蛋白的化学力学性质，以及细菌趋化性和植物纤维代谢的大分子复合物的结构和功能。值得注意的是，所有的项目都建立在之前大量工作的基础上。第一个项目将研究两个运动系统的机制：ClpX展开酶的蛋白质展开和细胞质动力蛋白的细胞骨架货物运输。化学感应阵列项目试图回答来自细菌表面的许多化学传感器的输入如何在阵列中被转导到数百纳米，从而引导细胞决定它是应该继续游泳还是改变方向，以适应不断变化的环境。纤维素项目旨在回答为什么与其他细菌产生的纤维素相比，人类肠道细菌产生如此复杂的纤维素。所有的项目都将利用计算方法来结合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冷冻电镜和亚细胞细胞器的低分辨率冷冻电镜断层扫描），产生大小为100纳米的结构的原子分辨率结构模型，包含1000 -1亿个原子。该项目的更广泛影响是不断开发广受欢迎（超过30万注册用户）的NAMD和VMD软件，再加上pi的长期培训工作，将使全世界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.