CDS&E: Adaptive Biomolecular Free Energy Simulations on Massive Computational Grids

天普大学的罗恩利维得到了化学系化学理论、模型和计算方法项目的支持，以开发强大的计算和统计工具，从根本上了解蛋白质如何在控制细胞过程中发挥作用。该项目由数学科学部数学和统计科学计划中的计算和数据支持科学与工程共同资助，并为国家战略计算计划做出贡献。 了解蛋白质的功能需要广泛调查的分子景观，控制哪些结构状态是功能性的，并知道与状态之间的转换，包括“活性”和“非活性”的蛋白质状态相关的自由能成本。该项目正在开发的基于随机重新加权的自适应计算技术，使其能够在由数十万个处理器组成的大型计算网格上，对蛋白质-配体结合和蛋白质构象自由能变化进行更可靠和准确的模拟，并在极端规模下进行模拟。这种能力在制药工业和生物技术中具有重要的应用。这项研究是在学术环境中进行的，学生们接受了最先进的模拟技术的培训。该研究的一个关键方面是创建和传播新的理论和计算方法，作为计算机脚本和程序免费提供给社区。该研究的重点是开发新的采样协议，用于在大规模但最低限度地通信的计算网格上进行生物分子模拟。这些算法的设计目标是从具有~ 5 K处理器的校园网格扩展到具有~ 500 K处理器的IBM World Community网格。 新的自由能重新加权技术的基础上的随机解的unbinned加权直方图分析方程正在制定可用于估计自由能从多态生物分子模拟，当模拟局部平衡，但不接近全球平衡的一些国家。Levy教授正在开发一种异步副本交换的自适应版本，该版本将自由能重新加权方程的随机解直接纳入用于传播轨迹的算法中。该项目解决了与使用专门为计算网格设计的多规范采样方案执行和分析生物分子模拟相关的重大计算和统计挑战，这些方案的大小从数千个处理器（校园网格）到数十万个处理器（IBM World Community Grid（WCG））。两个应用程序被用来说明新的方法和WCG上的实现：设计HIV-1整合酶的抑制剂，并探索激酶的功能转换的序列的影响。Levy教授通过美国和欧洲的暑期学校和研讨会提供新代码和技术的讲座和实践经验。 代码和脚本可以免费传播供模拟社区使用，并且可以与广泛使用的开源分子动力学代码（如GROMACS和OpenMM）接口。

Ron Levy of Temple University is supported by an award from the Chemical Theory, Models and Computational Methods Program in the Chemistry Division for the development of powerful computational and statistical tools to provide a fundamental understanding of how proteins function in controlling cellular processes. This project is co-funded by the Computational and Data-Enabled Science and Engineering in Mathematical and Statistical Sciences Program in the Division of Mathematical Sciences, and contributes to the National Strategic Computing Initiative. Understanding how proteins function requires extensive surveys of the molecular landscapes that control which structural states are functional, and knowing the free energy costs associated with transitions between states, including "active" and "inactive" protein states. The adaptive computational techniques based on stochastic reweighting that are being developed in this project make it possible to perform more reliable and accurate simulations of protein-ligand binding and conformational free energy changes of proteins, and to do so at extreme scale, on large computing grids consisting of hundreds of thousands of processors. This capability has important applications in the pharmaceutical industry and for biotechnology. The research is being carried out in an academic environment, where students are trained in state-of-the-art simulation techniques. A key aspect of the research is the creation and dissemination of the new theoretical and computational approaches, implemented as computer scripts and programs made freely available to the community.The focus of this research is on developing new sampling protocols for performing biomolecular simulations on massive but minimally communicating computational grids. The algorithms are designed to scale from campus grids with ~5K processors to the IBM World Community grid with ~500K processors. New free energy reweighting techniques based on stochastic solutions to the unbinned weighted histogram analysis equations are being formulated which can be used to estimate free energies from multi-state biomolecular simulations, when the simulations are locally equilibrated but not close to globally equilibrated at some of the states. Professor Levy is developing an adaptive version of asynchronous replica exchange that incorporates stochastic solutions to the free energy reweighting equations directly into the algorithms used to propagate the trajectories. This project addresses the significant computational and statistical challenges associated with performing and analyzing biomolecular simulations using multi-canonical sampling schemes designed specifically for use on computational grids, and which span sizes from thousands of processors (campus grids) to hundreds of thousands of processors (the IBM World Community Grid (WCG)). Two applications are used to illustrate the new approach and its implementation on the WCG: designing inhibitors of HIV-1 integrase, and exploring the effect of sequence on functional transitions in kinases. Professor Levy provides lectures and hands-on experience with the new codes and techniques through summer schools and workshops in the U.S. and Europe. Codes and scripts are freely disseminated for use by the simulation community, and can be interfaced to widely-used open source molecular dynamics codes such as GROMACS and OpenMM.