LONG TIME SIMULATIONS OF PROTEIN FOLDING: A SYNERGISTIC APPROACH

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子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个挑战。 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，因此解决蛋白质折叠的能力将对不同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巨大的进展，在毫秒级时间尺度上模拟了所有原子细节的蛋白质折叠。 在这里，我们建议协同融合MSM方法和ANTON独特的强大功能，以超越任何一种方法本身可以做的事情：我们建议在ANTON上运行一个单一的长轨迹，并使用Folding@home跟踪毫秒级的聚合MD。 我们提出了在显式溶剂中模拟BBL的折叠。 BBL是一个主要的目标，由于其丰富的实验数据，其潜在的作用，作为一个下坡（无障碍）文件夹，但仍有争议，由于潜在的相互冲突的实验数据。 如果成功的话，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，可能会揭示看似矛盾的实验，并更直接地阐明导致下坡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有效地和协同联合收割机HPC资源和分布式计算相结合，以及对许多其他分子模拟问题的影响。

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.