Approaches for computing small molecule binding free energies based on molecular simulations are now regularly being employed by academic and industry practitioners to study receptor-ligand systems and prioritize the synthesis of small molecules for ligand design. Given the variety of methods and implementations available, it is natural to ask how the convergence rates and final predictions of these methods compare. In this study, we describe the concept and results for the SAMPL6 SAMPLing challenge, the first challenge from the SAMPL series focusing on the assessment of convergence properties and reproducibility of binding free energy methodologies. We provided parameter files, partial charges, and multiple initial geometries for two octa-acid (OA) and one cucurbit[8]uril (CB8) host-guest systems. Participants submitted binding free energy predictions as a function of the number of force and energy evaluations for seven different alchemical and physical-pathway (i.e., potential of mean force and weighted ensemble of trajectories) methodologies implemented with the GROMACS, AMBER, NAMD, or OpenMM simulation engines. To rank the methods, we developed an efficiency statistic based on bias and variance of the free energy estimates. For the two small OA binders, the free energy estimates computed with alchemical and potential of mean force approaches show relatively similar variance and bias as a function of the number of energy/force evaluations, with the attach-pull-release (APR), GROMACS expanded ensemble, and NAMD double decoupling submissions obtaining the greatest efficiency. The differences between the methods increase when analyzing the CB8-quinine system, where both the guest size and correlation times for system dynamics are greater. For this system, nonequilibrium switching (GROMACS/NS-DS/SB) obtained the overall highest efficiency. Surprisingly, the results suggest that specifying force field parameters and partial charges is insufficient to generally ensure reproducibility, and we observe differences between seemingly converged predictions ranging approximately from 0.3 to 1.0 kcal/mol, even with almost identical simulations parameters and system setup (e.g., Lennard-Jones cutoff, ionic composition). Further work will be required to completely identify the exact source of these discrepancies. Among the conclusions emerging from the data, we found that Hamiltonian replica exchange-while displaying very small variance-can be affected by a slowly-decaying bias that depends on the initial population of the replicas, that bidirectional estimators are significantly more efficient than unidirectional estimators for nonequilibrium free energy calculations for systems considered, and that the Berendsen barostat introduces non-negligible artifacts in expanded ensemble simulations.

中文翻译：

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SAMPL6 SAMPLing 挑战：评估结合自由能计算的可靠性和效率。

基于分子模拟计算小分子结合自由能的方法现在经常被学术界和工业界从业者用来研究受体-配体系统，并优先考虑小分子的合成以进行配体设计。鉴于可用的方法和实现的多样性，很自然地会问这些方法的收敛速度和最终预测如何比较。在这项研究中，我们描述了 SAMPL6 SAMPLing 挑战的概念和结果，这是 SAMPL 系列的第一个挑战，重点是评估结合自由能方法的收敛特性和再现性。我们为两个八酸 (OA) 和一个葫芦 [8] uril (CB8) 主客体系统提供了参数文件、部分电荷和多个初始几何结构。参与者提交了结合自由能预测，作为使用 GROMACS、AMBER、NAMD 或 OpenMM 实施的七种不同炼金术和物理路径（即平均力的潜力和轨迹的加权集合）方法的力和能量评估数量的函数模拟引擎。为了对这些方法进行排序，我们基于自由能估计的偏差和方差开发了一个效率统计量。对于两个小的 OA 粘合剂，使用炼金术和平均力的潜力计算的自由能估计值显示出相对相似的方差和偏差作为能量/力评估数量的函数，具有附着-拉动-释放 (APR)、GROMACS扩展集成和 NAMD 双解耦提交获得最大效率。在分析 CB8-奎宁系统时，方法之间的差异会增加，其中客体大小和系统动力学的相关时间都更大。对于该系统，非平衡切换 (GROMACS/NS-DS/SB) 获得了整体最高效率。令人惊讶的是，结果表明，指定力场参数和部分电荷不足以确保可重复性，我们观察到看似收敛的预测之间的差异，范围约为 0.3 到 1.0 kcal/mol，即使模拟参数和系统设置几乎相同（例如， Lennard-Jones 截止值，离子组成）。需要进一步的工作来完全确定这些差异的确切来源。在从数据中得出的结论中，