Free energy perturbation (FEP)-based absolute binding free energy (ABFE) calculations have emerged as a powerful tool for the accurate prediction of ligand–protein binding affinities in drug discovery. The restraint addition is crucial in FEP-ABFE calculations; however, due to the non-orthogonal couplings between the restrained degrees of freedom, it typically requires numerous λ windows to ensure the phase-space overlap during restraint addition. This study introduces the RED-E-function-based equilibrium parameter finder (REPF), a novel method that relies on harmonic restraints to optimize the equilibrium values in restraints, enhancing phase-space overlap and improving the convergence of the restraint addition. REPF was applied to 44 protein–ligand complexes across 5 targets and compared to restraint schemes reported in the literature. We found that REPF-optimized restraints achieve an accuracy comparable to that of the 12λ approach while using only 2λ simulations, resulting in a significant reduction in computational costs. Extensive tests confirmed the improved convergence behavior and reduced energy fluctuations of REPF-optimized restraints.

中文翻译：

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基于 RED-E 函数的平衡参数查找器：在绝对束缚自由能计算中找到最佳约束参数


基于自由能扰动 （FEP） 的绝对结合自由能 （ABFE） 计算已成为药物发现中准确预测配体-蛋白质结合亲和力的强大工具。在 FEP-ABFE 计算中，约束添加至关重要;然而，由于约束自由度之间的非正交耦合，它通常需要许多 λ 窗口来确保在添加约束期间的相空间重叠。本研究引入了基于 RED-E 函数的平衡参数查找器 （REPF），这是一种依靠谐波约束来优化约束中平衡值的新方法，增强了相空间重叠并提高了约束添加的收敛性。REPF 应用于 5 个靶标的 44 种蛋白质-配体复合物，并与文献中报道的约束方案进行了比较。我们发现，REPF 优化的约束器在仅使用 2λ 模拟的情况下实现了与 12λ 方法相当的准确性，从而显著降低了计算成本。广泛的测试证实了 REPF 优化的约束装置改善了收敛行为并减少了能量波动。