The SAMPL6 SAMPLing challenge: assessing the reliability and efficiency of binding free energy calculations
The SAMPL6 SAMPLing challenge: assessing the reliability and efficiency of binding free energy calculations
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DOI：
10.1007/s10822-020-00290-5
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发表时间：
2020-01-27
影响因子：
3.5
通讯作者：
Chodera, John D.
中科院分区：
文献类型：
--
作者：
Rizzi, Andrea;Jensen, Travis;Chodera, John D.
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行业从业者用来研究受体-配体系统，并优先考虑用于配体设计的小分子的合成。考虑到可用的方法和实现的多样性，很自然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，我们描述的概念和结果的SAMPL 6采样的挑战，第一个挑战的SAMPL系列集中在评估的收敛性和结合自由能方法的再现性。我们提供了两个八酸（OA）和一个葫芦[8]脲（CB 8）主-客体系统的参数文件，部分电荷和多个初始几何形状。参与者提交了具有约束力的自由能预测，作为七种不同炼金术和物理途径的力和能量评估数量的函数（即，平均力势和轨迹加权系综）方法，使用GROMACS、AMBER、NAMD或OpenMM仿真引擎实现。为了对这些方法进行排名，我们开发了一个基于自由能估计的偏差和方差的效率统计。对于两个小的OA绑定器，自由能估计计算与炼金术和潜在的平均力的方法显示出相对相似的方差和偏差作为能量/力评估的数量的函数，与附着-拉动-释放（APR），GROMACS扩展合奏，NAMD双去耦提交获得最大的效率。当分析CB 8-奎宁系统时，方法之间的差异增加，其中系统动力学的客体尺寸和相关时间都更大。对于这个系统，非平衡开关（GROMACS/NS-DS/SB）获得了最高的整体效率。令人惊讶的是，结果表明，指定力场参数和部分电荷不足以通常确保再现性，并且我们观察到似乎收敛的预测之间的差异，范围约为0.3至1.0 kcal/mol，即使具有几乎相同的模拟参数和系统设置（例如，Lennard-Jones截止值，离子组成）。需要进一步开展工作，以彻底查明这些差异的确切来源。在从数据中得出的结论中，我们发现，汉密尔顿副本交换-虽然显示非常小的方差-可以受到缓慢衰减的偏差的影响，该偏差取决于副本的初始种群，对于所考虑的系统的非平衡自由能计算，双向估计比单向估计明显更有效，并且Berendsen恒压器在扩展的集合模拟中引入了不可忽略的伪像。
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.