LONG TIME SIMULATIONS OF PROTEIN FOLDING: A SYNERGISTIC APPROACH

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 几十年来，模拟蛋白质折叠的动力学一直是一项挑战。此外，由于蛋白质折叠是一个与许多领域相关的标志性问题，解决蛋白质折叠的能力将在不同的领域产生广泛的影响。在过去的5年里，马尔可夫状态模型(MSM)方法在该领域取得了戏剧性的进展，产生了在毫秒级上对蛋白质折叠的全原子细节的模拟。在这里，我们建议将MSM方法和Anton独特的强大功能协同融合，以超越这两种方法单独可以做的事情：我们建议在Anton上运行一个单独的长轨迹，并使用Folding@Home跟踪几毫秒的聚合MD。我们建议模拟BBL在显性溶剂中的折叠。BBL是一个主要的目标，因为它有丰富的实验数据，它潜在的作用是一个下坡(无障碍)文件夹，但由于潜在的相互冲突的实验数据，它仍然存在争议。如果成功，结果将是一个关于这种蛋白质如何折叠的完全详细的模型，可能会揭示这些看似矛盾的实验，并更直接地阐明导致下行折叠的突变体的化学性质。最重要的是，这项工作将展示如何高效和协同地结合HPC资源和分布式计算，并对许多其他分子模拟问题产生影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Simulating the dynamics of protein folding has been a challenge for decades. Moreover, since protein folding is an iconic problem with connections to many fields, the ability to tackle protein folding will have a broad impact across diverse fields. Over the last 5 years, there has been dramatic progress in the field with Markov State Model (MSM) approaches, yielding simulations of protein folding in all-atom detail, on the millisecond timescale. Here, we propose to synergistically fuse MSM approaches and the uniquely powerful capabilities of ANTON in order to go beyond what either method could do on its own: we propose to run a single, long trajectory on ANTON and follow up with milliseconds of aggregate MD using Folding@home. We proposed to simulate the folding of BBL in explicit solvent. BBL is a prime target due to its wealth of experimental data, its potential role as a downhill (barrier free) folder, but yet still controversial due to potentially conflicting experimental data. If successful, the result would be a fully detailed model for how this protein folds, potentially shedding light on the seemingly contradictory experiments as well as elucidating more directly the chemical nature of the mutants which lead to downhill folding. Most significantly, this work would demonstrate how to efficiently and synergistically combine HPC resources and distributed computing, with implications for many other molecular simulation problems as well.