CDI-Type II: Mapping Complex Biomolecular Reactions with Large Scale Replica Exchange Simulations on National Production Cyberinfrastructure

在原子级分辨率水平上对复杂的生物和化学现象进行大规模、逼真的模拟，是分子模拟的一个巨大挑战。 构象空间的有效采样可能需要大量的相互耦合的计算密集型模拟。 基于偏置力和副本交换广义系综的应用的增强型构象采样算法，其中大量的系统副本被并行模拟，是研究各种物理化学过程的最强大的方法之一。 目前使用的解耦方法收敛非常缓慢，并且由于独立模拟彼此不平衡，因此可靠性往往令人怀疑。 副本交换（RE）算法的关键方面是系统的副本周期性地交换它们的状态参数，使它们能够快速遍历构象空间并增强平衡。然而，目前广泛使用的RE方法的同步公式在涉及许多交换副本时的可扩展性和控制方面受到高度限制。这种限制排除了使用RE模拟新的应用领域，需要计算的高维自由能表面，并需要动态控制103 - 104副本的景观演变。 这个项目涉及到一个强大的自适应力偏置程序的发展，加上异步副本交换方法。 该研究团队正在开发一种新型的基础设施，即REFW交换框架（REFW），以实现在广泛的生产计算资源上执行超大规模RE模拟，包括但不限于NSF TeraGrid（及其继任者XD），云和校园级集群环境，以及即将推出的Blue沃茨超级计算机。 REFW正被应用于呈现多层次复杂性的应用，如glmS核酶/核糖开关中的偶联配体结合、构象变化和催化，这是迄今为止不可能实现的。该研究团队创建的网络基础设施能够逼真地模拟重要的生物过程，这些过程在生物学、生物物理学、药物化学、和生物物理学有可能影响人类健康。此外，REWF还可以应用于许多其他越来越依赖真实模拟的科学领域，包括催化，地震预测和石油工程。该项目还培训下一代计算科学家，以应用这些方法来解决高影响力的跨学科研究问题。由此产生的技术和培训使研究一系列前所未有的复杂性的新反应化学问题成为可能，并通过先进的计算极大地促进了创新和发现。这是一个网络驱动的发现和创新计划奖，由数学和物理科学理事会的化学部和物理部共同资助。

Large scale, realistic simulations of complex biological and chemical phenomena at the atomic level of resolution level present a grand challenge for molecular simulation. Effective sampling of conformational space may require large numbers of computationally intensive simulations which are coupled to one another. Enhanced conformational sampling algorithms based on the application of biasing forces and replica exchange generalized ensembles, whereby a large number of replicas of the system are simulated in parallel, among the most powerful methods to study a wide variety of physicochemical processes. Uncoupled methods currently in use are very slowly convergent and often of dubious reliability as the independent simulations are not in equilibrium with one another. The key aspect of replica exchange (RE) algorithms is that replicas of the system periodically exchange their state parameters allowing them to rapidly traverse conformational space and to enhance equilibration. Current synchronous formulations of the RE method in wide use, however, are highly limited in terms of scalability and control when many exchanging replicas are involved. This limitation precludes the use of RE simulations to new application areas that require the calculation of high-dimensional free energy surfaces, and necessitate the dynamic control of 103-104 replicas as the landscape evolves. This project involves the development of a robust adaptive force biasing procedure coupled with an asynchronous replica exchange method. The research team is developing a novel infrastructure, the Replica Exchange Frame work (REFW) to enable the execution of very large scale RE simulations on a broad range of production computational resources, including but not limited to NSF TeraGrid (and its successor XD), cloud and campus-level cluster environments, as well as the forthcoming Blue Waters supercomputer. The REFW is being applied to applications that present multiple levels of complexity, such as coupled ligand binding, conformational change and catalysis in the glmS ribozyme/riboswitch that were hitherto not possible.The cyberinfrastructure created by this research team enables realistic simulations of important biological processes that have relevance in many areas of biology, biophysics, medicinal chemistry, and biophysics with the potential to impact human health. Additionally, the REWF may be applied in many other scientific areas that increasingly rely on realistic simulation including catalysis, earthquake prediction and petroleum engineering. The project is also training the next generation of computational scientists to apply these methods to solve high-impact interdisciplinary research problems. The resulting technology and training enables the study of a host of new reactive chemical problems of unprecedented complexity, and greatly facilitates innovation and discovery through advanced computation.This is a Cyber-Enabled Discovery and Innovation Program award and is co-funded by the Division of Chemistry and the Division of Physics in the Directorate for Mathematical and Physical Sciences.