Biomolecular Simulations Group, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, 11400, Uruguay.
Institute of Chemistry and Center for Computational Engineering & Science, University of Campinas, Rua Josué de Castro s/n, Cidade Universitária "Zeferino Vaz", Barão Geraldo, 13083-861 Campinas, SP, Brazil.
J Chem Inf Model. 2021 Jan 25;61(1):408-422. doi: 10.1021/acs.jcim.0c01205. Epub 2021 Jan 8.
Simulating huge biomolecular complexes of million atoms at relevant biological time scales is becoming accessible to the broad scientific community. That proves to be crucial for urgent responses against emergent diseases in real time. Yet, there are still issues to sort regarding the system setup so that molecular dynamics (MD) simulations can be run in a simple and standard way. Here, we introduce an optimized pipeline for building and simulating enveloped virus-like particles (VLP). First, the membrane packing problem is tackled with new features and optimized options in PACKMOL. This allows preparing accurate membrane models of thousands of lipids in the context of a VLP within a few hours using a single CPU. Then, the assembly of the VLP system is done within the multiscale framework of the coarse-grained SIRAH force field. Finally, the equilibration protocol provides a system ready for production MD simulations within a few days on broadly accessible GPU resources. The pipeline is applied to study the Zika virus as a test case for large biomolecular systems. The VLP stabilizes at approximately 0.5 μs of MD simulation, reproducing correlations greater than 0.90 against experimental density maps from cryo-electron microscopy. Detailed structural analysis of the protein envelope also shows very good agreement in root-mean-square deviations and B-factors with the experimental data. The level of details attained shows for the first time a possible role for anionic phospholipids in stabilizing the envelope. Combining an efficient and reliable setup procedure with an accurate coarse-grained force field provides a valuable pipeline for simulating arbitrary viral systems or subcellular compartments, paving the way toward whole-cell simulations.
模拟具有数百万个原子的大型生物分子复合物，并达到相关的生物学时间尺度，正逐渐为广大科学界所接受。这对于实时应对新出现的传染病至关重要。然而，在系统设置方面仍存在一些问题，以便可以以简单和标准的方式运行分子动力学（MD）模拟。在这里，我们引入了一种优化的包膜病毒样颗粒（VLP）构建和模拟的流水线。首先，通过 PACKMOL 中的新功能和优化选项来解决膜包装问题。这允许在数小时内使用单个 CPU 为 VLP 准备数千个脂质的准确膜模型。然后，在粗粒 SIRAH 力场的多尺度框架内完成 VLP 系统的组装。最后，平衡协议提供了一个系统，可在几天内在广泛可用的 GPU 资源上进行生产 MD 模拟。该流水线应用于研究寨卡病毒作为大型生物分子系统的测试案例。VLP 在大约 0.5 μs 的 MD 模拟中稳定，与冷冻电子显微镜的实验密度图的相关性大于 0.90。蛋白质包膜的详细结构分析也显示出与实验数据在均方根偏差和 B 因子方面非常吻合。所达到的细节水平首次表明阴离子磷脂在稳定包膜方面可能起作用。结合高效可靠的设置过程和准确的粗粒力场，为模拟任意病毒系统或亚细胞区室提供了有价值的流水线，为全细胞模拟铺平了道路。
