Computational Biochemistry, Center of Medical Biotechnology, University of Duisburg-Essen, Essen 45141, Germany.
J Chem Theory Comput. 2020 Mar 10;16(3):1396-1410. doi: 10.1021/acs.jctc.9b00725. Epub 2020 Feb 28.
The Central Limit Free Energy Perturbation (CL-FEP) approach, based on the Free Energy Perturbation (FEP) theory and the Central Limit (CL) theorem, allows evaluating the FEP identity directly from the energy samples of the end states of a system transformation. In CL-FEP, energies obtained from explicit solvent simulations are used to estimate the absolute free energy change. No fitted parameters are introduced in our implementation, and no stratification is needed to obtain accurate free energy evaluations. We first illustrate the applicability of CL-FEP in four dissimilar benchmark systems from host-guest to proteins-peptide complexes, for which the deviation from the experimental values was below 1 kcal/mol. Next, we extended the validation to three sets of complexes comprising 25 host-guest and protein-ligand systems. There, the mean absolute error of the free energy changes calculated with CL-FEP is between 1.1 and 1.4 kcal/mol among the different sets, which is in the range of accuracy of the most reliable free energy approaches applied to these systems. CL-FEP is an unbiased free energy change estimator that also profits from a bootstrapping algorithm, which makes the evaluation of convergence and confidence an inherent component of the procedure. Finally, we developed CLFEP.pl, an automatic tool to compute free energy changes directly from the energy output of standard molecular dynamics simulations.
基于自由能微扰（FEP）理论和中心极限（CL）定理的无约束自由能微扰（CL-FEP）方法允许直接从系统转变的终态的能量样本评估 FEP 恒等式。在 CL-FEP 中，使用来自显式溶剂模拟的能量来估计绝对自由能变化。我们的实现中没有引入拟合参数，也不需要分层来获得准确的自由能评估。我们首先在四个不同的基准系统（从主体-客体到蛋白质-肽复合物）中说明了 CL-FEP 的适用性，对于这些系统，与实验值的偏差低于 1 kcal/mol。接下来，我们将验证扩展到三个包含 25 个主体-客体和蛋白质-配体系统的集合。在这些集合中，CL-FEP 计算的自由能变化的平均绝对误差在不同集合之间在 1.1 到 1.4 kcal/mol 之间，这在应用于这些系统的最可靠的自由能方法的精度范围内。CL-FEP 是一种无偏的自由能变化估计量，它还受益于自举算法，这使得评估收敛性和置信度成为该过程的固有组成部分。最后，我们开发了 CLFEP.pl，这是一种自动工具，可以直接从标准分子动力学模拟的能量输出计算自由能变化。
