Biomolecular Simulations under Realistic Macroscopic Salt Conditions
Biomolecular Simulations under Realistic Macroscopic Salt Conditions
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DOI：
10.1021/acs.jpcb.7b11734
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发表时间：
2018-05-31
影响因子：
3.3
通讯作者：
Chodera, John D.
中科院分区：
文献类型：
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作者：
Ross, Gregory A.;Rustenburg, Arien S.;Chodera, John D.
生物分子模拟通常在水性环境中进行，其中离子的数量在模拟的持续时间内保持固定，通常具有最低限度中和离子环境或旨在匹配宏观盐浓度的盐对的数量。相比之下，真实的生物分子经历局部离子环境，其中盐浓度是动态的并且可能与本体不同。盐浓度变化的程度和与宏观浓度的平均偏差仍然是未知的。在这里，我们描述的理论和实施的Monte Carlo随机统计，可以添加到显式溶剂分子动力学或Monte Carlo模拟样品从一个semigrand正则系综中的盐对的数量波动动态模拟过程中。该模拟器再现了模拟体积的正确平衡统计数据，该模拟体积可以在定义的宏观盐浓度下与大型储层交换离子。为了实现有用的Monte Carlo接受率，该方法利用非平衡候选Monte Carlo（NCMC）移动，其中单价离子和水分子使用短非平衡轨迹进行炼金术转化，其中修改的Metropolis-Hastings标准确保（Delta mu，N，p，T）系综的正确平衡统计以实现接受率的类似于10（46）x的提升。我们展示了典型的蛋白质（DHFR和酪氨酸激酶Src）和核酸（Drew-Dickerson B-DNA十二聚体）系统如何表现出盐浓度分布，显着不同于固定盐散装模拟和显示波动是在相同的数量级的平均值。
Biomolecular simulations are typically performed in an aqueous environment where the number of ions remains fixed for the duration of the simulation, generally with either a minimally neutralizing ion environment or a number of salt pairs intended to match the macroscopic salt concentration. In contrast, real biomolecules experience local ion environments where the salt concentration is dynamic and may differ from bulk. The degree of salt concentration variability and average deviation from the macroscopic concentration remains, as yet, unknown. Here, we describe the theory and implementation of a Monte Carlo osmostat that can be added to explicit solvent molecular dynamics or Monte Carlo simulations to sample from a semigrand canonical ensemble in which the number of salt pairs fluctuates dynamically during the simulation. The osmostat reproduces the correct equilibrium statistics for a simulation volume that can exchange ions with a large reservoir at a defined macroscopic salt concentration. To achieve useful Monte Carlo acceptance rates, the method makes use of nonequilibrium candidate Monte Carlo (NCMC) moves in which monovalent ions and water molecules are alchemically transmuted using short nonequilibrium trajectories, with a modified Metropolis-Hastings criterion ensuring correct equilibrium statistics for an (Delta mu, N, p, T) ensemble to achieve a similar to 10(46)x boost in acceptance rates. We demonstrate how typical protein (DHFR and the tyrosine kinase Src) and nucleic acid (Drew-Dickerson B-DNA dodecamer) systems exhibit salt concentration distributions that significantly differ from fixed-salt bulk simulations and display fluctuations that are on the same order of magnitude as the average.