Implicit ligand theory describes the relationship between the noncovalent binding free energy and the binding free energy between a ligand and multiple rigid receptor conformations. We have previously shown that if the receptor conformations are sampled from or reweighed to a holo ensemble, the binding free energy relative to the ligand that defines the ensemble can be calculated. Here, we apply a variance reduction technique known as control variates to derive a new statistical estimator for the relative binding free energy. In applications to a data set of 6 reference ligands and 18 test ligands, statistically significant differences between the estimators are not observed for most systems. However, in cases where such differences are observed, the new estimator is more accurate, precise, and converges more quickly. Performance improvements are most consistent where there is a clear correlation, with a correlation coefficient greater than 0.3, between the control variate and the statistic being averaged.

隐式配体理论描述了非共价结合自由能与配体和多个刚性受体构象之间的结合自由能之间的关系。先前我们已经表明，如果从整体集合中取样或重新称重受体构象，则可以计算相对于限定该集合的配体的结合自由能。在这里，我们应用称为控制变量的方差减少技术来得出相对结合自由能的新统计估计量。在将数据应用于6个参考配体和18个测试配体的数据集时，大多数系统未观察到统计量之间的显着差异。但是，在观察到这种差异的情况下，新的估算器更加准确，精确，并且收敛速度更快。