Enhanced Jarzynski free energy calculations using weighted ensemble.
Enhanced Jarzynski free energy calculations using weighted ensemble.
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DOI：
10.1063/5.0020600
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发表时间：
2020-10
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影响因子：
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通讯作者：
Nicole M. Roussey;Alex Dickson
中科院分区：
文献类型：
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作者：
Nicole M. Roussey;Alex Dickson
稳定状态之间的跃迁自由能是决定正向和反向反应的相对概率以及平衡状态概率比的关键热力学量。药物及其受体的结合自由能是特别感兴趣的，因为它作为药物设计的优化函数。多年来，已经开发了许多计算方法来计算结合自由能，虽然许多这些方法有很长的历史，问题，如收敛的自由能估计和投影的结合过程中的顺序参数仍然存在。20多年前，Jarzynski等式被导出，承诺通过测量应用于短非平衡轨道的功来计算平衡自由能。然而，发现这些计算主要由应用功较低的轨迹主导，这些轨迹发生的概率极低。在这里，我们研究加权集成算法与Jarzynski等式的组合。在这种结合的方法中，一个合奏的非平衡轨迹并行运行，克隆和合并操作被用来优先采样占主导地位的自由能计算的低功轨迹。两个额外的方法也检查：（i）一种新的加权系综重采样器，样本轨迹直接根据其重要性的工作的工作和（ii）扩散蒙特卡罗方法使用的应用工作作为选择潜力。我们彻底检查了一系列模型Lennard-Jones原子对的解束缚自由能计算的准确性和效率，相互作用强度范围从2千卡/摩尔到20千卡/摩尔。我们发现，加权系综计算可以更有效地确定准确的结合自由能，特别是更深的Lennard-Jones阱深度。
The free energy of transitions between stable states is the key thermodynamic quantity that governs the relative probabilities of the forward and reverse reactions and the ratio of state probabilities at equilibrium. The binding free energy of a drug and its receptor is of particular interest, as it serves as an optimization function for drug design. Over the years, many computational methods have been developed to calculate binding free energies, and while many of these methods have a long history, issues such as convergence of free energy estimates and the projection of a binding process onto order parameters remain. Over 20 years ago, the Jarzynski equality was derived with the promise to calculate equilibrium free energies by measuring the work applied to short nonequilibrium trajectories. However, these calculations were found to be dominated by trajectories with low applied work that occur with extremely low probability. Here, we examine the combination of weighted ensemble algorithms with the Jarzynski equality. In this combined method, an ensemble of nonequilibrium trajectories are run in parallel, and cloning and merging operations are used to preferentially sample low-work trajectories that dominate the free energy calculations. Two additional methods are also examined: (i) a novel weighted ensemble resampler that samples trajectories directly according to their importance to the work of work and (ii) the diffusion Monte Carlo method using the applied work as the selection potential. We thoroughly examine both the accuracy and efficiency of unbinding free energy calculations for a series of model Lennard-Jones atom pairs with interaction strengths ranging from 2 kcal/mol to 20 kcal/mol. We find that weighted ensemble calculations can more efficiently determine accurate binding free energies, especially for deeper Lennard-Jones well depths.