Massive-Scale Binding Free Energy Simulations of HIV Integrase Complexes Using Asynchronous Replica Exchange Framework Implemented on the IBM WCG Distributed Network
Massive-Scale Binding Free Energy Simulations of HIV Integrase Complexes Using Asynchronous Replica Exchange Framework Implemented on the IBM WCG Distributed Network
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DOI：
10.1021/acs.jcim.8b00817
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发表时间：
2019-04-01
影响因子：
5.6
通讯作者：
Levy，Ronald M.
中科院分区：
文献类型：
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作者：
Xia，Junchao;Flynn，William;Levy，Ronald M.
为了进行蛋白质-配体复合物结合自由能的大规模复制交换分子动力学（REMD）模拟，在IBM World Community Grid（WCG）上实现了结合能分布分析方法（BEDAM）的异步复制交换（AsyncRE）框架，并优化了模拟参数，以减少开销并提高WCG AsyncRE模拟的预测能力.我们还使用WCG分布式计算网格和来自SAMPL4挑战的301个配体进行了第一次大规模结合自由能计算，用于HIV-1整合酶复合物的大规模结合自由能预测。总共有10000个模拟的复合体，101万个副本，以及102000 μ s的聚合MD模拟。在WCG上运行AsyncRE MD模拟需要在可以运行的副本数量（广度）和每个副本可以完成的完整RE周期数量（深度）之间进行权衡。与运行在紧密耦合集群（如XSEDE）上的同步数据交换（SyncRE）相比，在WCG上，可以在异构分布式硬件上同时启动更多的副本，但每个完整的RE周期需要更多的开销。我们将WCG的结果与AutoDock和更先进的RE模拟的结果进行了比较，包括使用平坦化电位来加速对与高能量垒导致的缓慢动力学相关的配体和/或受体的选定自由度的采样。我们提出了一个合适的策略，RE模拟细化高吞吐量的对接结果，可以匹配到相应的计算资源：从HPC集群，小型或中型分布式校园网格，最后到大规模的计算网络，包括数以百万计的CPU像WCG上可用的资源。
To perform massive-scale replica exchange molecular dynamics (REMD) simulations for calculating binding free energies of protein–ligand complexes, we implemented the asynchronous replica exchange (AsyncRE) framework of the binding energy distribution analysis method (BEDAM) in implicit solvent on the IBM World Community Grid (WCG) and optimized the simulation parameters to reduce the overhead and improve the prediction power of the WCG AsyncRE simulations. We also performed the first massive-scale binding free energy calculations using the WCG distributed computing grid and 301 ligands from the SAMPL4 challenge for large-scale binding free energy predictions of HIV-1 integrase complexes. In total there are ∼10000 simulated complexes, ∼1 million replicas, and ∼2000 μs of aggregated MD simulations. Running AsyncRE MD simulations on the WCG requires accepting a trade-off between the number of replicas that can be run (breadth) and the number of full RE cycles that can be completed per replica (depth). As compared with synchronous Replica Exchange (SyncRE) running on tightly coupled clusters like XSEDE, on the WCG many more replicas can be launched simultaneously on heterogeneous distributed hardware, but each full RE cycle requires more overhead. We compared the WCG results with that from AutoDock and more advanced RE simulations including the use of flattening potentials to accelerate sampling of selected degrees of freedom of ligands and/or receptors related to slow dynamics due to high energy barriers. We propose a suitable strategy of RE simulations to refine high throughput docking results which can be matched to corresponding computing resources: from HPC clusters, to small or medium-size distributed campus grids, and finally to massive-scale computing networks including millions of CPUs like the resources available on the WCG.