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体，其中没有一个是活的。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。 有了蓝色沃茨，现在可以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迈出最关键的一步。 通过分子动力学模拟的“计算显微镜”来探索生命系统的能力不仅对基础科学的进步有着深远的影响，而且对疾病的治疗和药物的开发也有着深远的影响。本项目将使用Blue沃茨来研究三种类型的生物分子系统：构成细胞骨架的微管，充当“细菌大脑”的化学传感器阵列，以及两种高度相关的逆转录病毒：HIV（人类免疫缺陷病毒）和RSV（劳斯肉瘤病毒）。 第一个项目将模拟天然形式的微管，以及微管、其调节伙伴和抗癌药物之间的相互作用。微管及其与药物相互作用的模拟可以帮助推动新的微管攻击癌症疗法的发展。 病毒项目的HIV部分建立在先前成功的完整HIV衣壳建模的基础上，以评估HIV药物对衣壳稳定性的影响，并模拟衣壳和宿主细胞因子之间的基本相互作用。HIV感染的模拟为开发新的HIV治疗方法提供了必要的详细信息。 RSV病毒项目的一部分已经构建了第一个病毒衣壳成熟中间阶段的模型，该模型将用于描述逆转录病毒的成熟过程，可能为攻击该成熟过程的新型抗病毒药物打开大门。 化学传感器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的数百纳米范围内进行转换，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。 化学传感器阵列是细菌中的一种通用结构，但在真核生物中并不存在，它为抗生素药物提供了一个新的靶点--在对抗细菌对当前抗生素的耐药性方面取得了迫切需要的进展。每一个提出的项目都为千万亿次计算为人类做出贡献提供了机会。并回答人类最古老的问题之一：“生命是什么？"

Cells are the building blocks of life, yet they are themselves acollection of proteins, small molecules, and solvent, none of whichare, in and of themselves, 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 scientificsupercomputing has offered the chance to study living systems at thelevels of atoms, cells, and all levels in between.  With Blue Waters,it is now possible to take the most critical step from inanimate toanimate matter by describing assembly and cooperation of thousands ofmacromolecules made of billions of atoms.  The ability to exploreliving systems via the "computational microscope" of moleculardynamics simulations has a profound impact not only on the progress ofbasic science, but also in the treatment of disease and thedevelopment of drugs.This project will use Blue Waters to study three types of biomolecularsystems: the microtubules that make up the cell's cytoskeleton, thechemosensory array that acts as a "bacterial brain", and two highlyrelevant retroviruses: HIV (human immunodeficiency virus) and RSV(Rous sarcoma virus).  The first project will model microtubules, intheir native form, as well as the interactions between themicrotubule, its regulatory partners, and anti-cancer agents.Simulations of the microtubule and its interactions with drugs canhelp drive the development of new microtubule-attacking cancertherapies.  The HIV part of the virus project builds on prior successin modeling the full HIV capsid to evaluate the effects of HIV drugson capsid stability and to model the essential interactions betweenthe capsid and host cell factors. Simulations of the HIV capsidprovide the necessary detailed knowledge of the vital infectionprocess to develop new HIV therapies.  The RSV part of the virusproject has constructed the first model of an intermediate stage invirus capsid maturation, which will be used to describe the maturationprocess of retroviruses may open the doors to a new type of anti-viraldrug which attacks that maturation process.  The chemosensory arrayproject seeks to answer how input from many chemical sensors on thebacterial surface are transduced across hundreds of nanometers in thearray, leading the cell to decide if it should continue swimming orchange direction, to adapt to changing environments.  The chemosensoryarray is a universal structure in bacteria, but absent in eukaryotes,offering a new target for antibiotic drugs - a desperately neededadvancement in combating bacterial resistance to current antibiotics.Each of the projects proposed presents an opportunity for petascalecomputing to contribute to mankind?s health and to answer one ofmankind's oldest questions: "What is life?"