Free-energy differences between pairs of end-states can be estimated based on molecular dynamics (MD) simulations using standard pathway-dependent methods such as thermodynamic integration (TI), free-energy perturbation, or Bennett’s acceptance ratio. Replica-exchange enveloping distribution sampling (RE-EDS), on the other hand, allows for the sampling of multiple end-states in a single simulation without the specification of any pathways. In this work, we use the RE-EDS method as implemented in GROMOS together with generalized AMBER force-field (GAFF) topologies, converted to a GROMOS-compatible format with a newly developed GROMOS++ program amber2gromos, to compute relative hydration free energies for a series of benzene derivatives. The results obtained with RE-EDS are compared to the experimental data as well as calculated values from the literature. In addition, the estimated free-energy differences in water and in vacuum are compared to values from TI calculations carried out with GROMACS. The hydration free energies obtained using RE-EDS for multiple molecules are found to be in good agreement with both the experimental data and the results calculated using other free-energy methods. While all considered free-energy methods delivered accurate results, the RE-EDS calculations required the least amount of total simulation time. This work serves as a validation for the use of GAFF topologies with the GROMOS simulation package and the RE-EDS approach. Furthermore, the performance of RE-EDS for a large set of 28 end-states is assessed with promising results.

中文翻译：

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使用广义 AMBER 力场拓扑的副本交换包络分布采样：在大分子集的相对水合自由能计算中的应用

末端状态对之间的自由能差异可以基于分子动力学 (MD) 模拟使用标准路径相关方法（例如热力学积分 (TI)、自由能扰动或 Bennett 接受率）来估计。另一方面，副本交换包络分布采样 (RE-EDS) 允许在单个模拟中对多个最终状态进行采样，而无需指定任何路径。在这项工作中，我们使用在 GROMOS 中实现的 RE-EDS 方法以及广义 AMBER 力场 (GAFF) 拓扑，通过新开发的 GROMOS++ 程序amber2gromos转换为与 GROMOS 兼容的格式，计算一系列苯衍生物的相对水合自由能。使用 RE-EDS 获得的结果与实验数据以及文献中的计算值进行了比较。此外，将估计的水和真空中的自由能差异与使用 GROMACS 进行的 TI 计算值进行比较。发现使用 RE-EDS 获得的多个分子的水合自由能与实验数据和使用其他自由能方法计算的结果非常一致。虽然所有考虑的自由能方法都提供了准确的结果，但 RE-EDS 计算所需的总模拟时间最少。这项工作是对 GROMOS 模拟包和 RE-EDS 方法使用 GAFF 拓扑的验证。此外，