Alchemically derived free energies are artifacted when the perturbed moiety has a nonzero net charge. The source of the artifacts lies in the effective treatment of the electrostatic interactions within and between the perturbed atoms and remaining (partial) charges in the simulated system. To treat the electrostatic interactions effectively, lattice‐summation (LS) methods or cutoff schemes in combination with a reaction‐field contribution are usually employed. Both methods render the charging component of the calculated free energies sensitive to essential parameters of the system like the cutoff radius or the box side lengths. Here, we discuss the results of three previously published studies of ligand binding. These studies presented estimates of binding free energies that were artifacted due to the charged nature of the ligands. We show that the size of the artifacts can be efficiently calculated and raw simulation data can be corrected. We compare the corrected results with experimental estimates and nonartifacted estimates from path‐sampling methods. Although the employed correction scheme involves computationally demanding continuum‐electrostatics calculations, we show that the correction estimate can be deduced from a small sample of configurations rather than from the entire ensemble. This observation makes the calculations of correction terms feasible for complex biological systems. To show the general applicability of the proposed procedure, we also present results where the correction scheme was used to correct independent free energies obtained from simulations employing a cutoff scheme or LS electrostatics. In this work, we give practical guidelines on how to apply the appropriate corrections easily.

中文翻译：

---

在配体结合自由能的计算中校正由于净电荷变化引起的静电伪影

当被扰动的部分具有非零净电荷时，炼金术衍生的自由能被人为产生。伪影的来源在于对模拟系统中扰动原子和剩余（部分）电荷内部和之间的静电相互作用的有效处理。为了有效地处理静电相互作用，通常采用晶格求和 (LS) 方法或结合反应场贡献的截止方案。这两种方法都使计算出的自由能的充电分量对系统的基本参数（如截止半径或盒子边长）敏感。在这里，我们讨论了三项先前发表的配体结合研究的结果。这些研究提供了由于配体带电性质而造成的结合自由能的估计值。我们表明可以有效地计算工件的大小并且可以更正原始模拟数据。我们将校正结果与路径采样方法的实验估计和非人工估计进行比较。尽管采用的校正方案涉及计算要求高的连续静电计算，但我们表明可以从配置的小样本而不是整个集合中推导出校正估计。这一观察使得校正项的计算对于复杂的生物系统是可行的。为了显示所提出程序的普遍适用性，我们还提供了结果，其中校正方案用于校正从采用截止方案或 LS 静电的模拟中获得的独立自由能。在这项工作中，