Studying the Role of Water Dynamics on the Protein Folding Mechanism Using Worldwide Distributed Computing

该项目由分子与细胞生物科学部的分子生物物理项目和化学部的理论与计算化学项目共同资助，将利用计算机模拟研究水在折叠机制中的作用。具体而言，通过大规模并行模拟，将在数十微秒的时间尺度上研究小而快速折叠的蛋白质的折叠。此外，有关水的作用的假设也将得到检验。例如，水是在过渡态中起结构作用，还是仅仅作为疏水的介电介质？先前的工作提出了许多可能性，包括水分子在压实和折叠过程中的逃逸作用，水-蛋白质氢键，单个水分子的离散方面和疏水效应，以及水的润滑作用。随着新的模拟技术和计算方法，这些想法将被探索，并有望发现新的机械方面。在蛋白质发挥其生物功能之前，它们必须自我组装或“折叠”。由于水的性质，理解蛋白质如何折叠变得很复杂。虽然水起初看起来像是一种简单的液体，但它具有许多非凡而复杂的特性。这些性质，包括疏水效应和氢键，可能只有通过复杂的、“明确的”水模型才能正确理解。然而，到目前为止，这些模型过于复杂，无法用于理解长时间尺度的行为，如蛋白质折叠。为了克服这些时间限制，我们创建了一个分布式计算项目。这个名为“Folding@Home”的项目现在拥有大约10万台个人电脑的能力，这种巨大的计算能力与新颖的算法相结合，应该可以让人们第一次模拟水在蛋白质折叠中的作用。此外，分布式计算允许在科学和公众之间进行一种新的“合作”。为了促进这种积极的合作，PI积极为参与者维护一个“聊天室”以及许多网络资源，以更好地了解蛋白质和蛋白质折叠。这与NSF倡导的许多更广泛的影响标准直接相关，包括在促进教学的同时推进发现和理解的目标，增强研究和教育的基础设施（分布式计算基础设施本身），广泛的传播以增强科学的理解（由人们为分布式计算项目贡献时间的参与和他们对正在进行的工作的直接兴趣所带来和鼓励）。

In this project, funded jointly by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences and the Theoretical and Computational Chemistry Program in the Chemistry Division, the role of water in the folding mechanism will be investigated using computer simulation. Specifically, through large-scale massively parallel simulation, the folding of small, fast-folding proteins will be investigated on the tens of microsecond timescale. In addition, hypotheses regarding the role of water will be tested. For example, does water play a structural role in the transition state or does water merely act as a hydrophobic, dielectric medium? Previous work has suggested many possibilities, including the role of the escape of water molecules during compaction and folding, water-protein hydrogen bonding, the discrete aspects of individual water molecules and the hydrophobic effect, and lubrication effects of water. With novel simulation techniques and computational methods, these ideas will be explored and hopefully novel mechanistic aspects will be discovered.Before proteins can carry out their biological function, they must self-assemble, or "fold." Understanding how proteins fold is complicated by the nature of water. While water at first may seem like a simple liquid, it has many remarkable and complex properties. These properties, including the hydrophobic effect and hydrogen boding, can likely only be correctly understood with complex, "explicit" models for water. However, these models to date have been too complex to use in understanding long timescale behavior, such as protein folding. To overcome these timescales, a distributed computing project was created. This project, called "Folding@Home," now has approximately the power of 100,000 PCs and this vast computing power combined with novel algorithms should allow one to simulate the role of water in protein folding for the first time. Moreover, distributed computing allows for a novel "collaboration" between science and the general public. To help foster this active collaboration, the PI actively maintains a "chat room" for participants as well as many web resources to better understand proteins and protein folding. This directly connects with many of the broader impact criteria championed by NSF, including the goals of advancing discovery and understanding while promoting teaching, enhancing infrastructure for research and education (the distributed computing infrastructure itself), and broad dissemination to enhance scientific understanding (brought about and encouraged by the participation of people donating their time for the distributed computing project and their direct interest in the work being performed).