Departamento de Química Física y Analítica , Universidad de Oviedo , Avda. Julián Clavería 8 , Oviedo , Asturias 33006 , Spain.
J Chem Inf Model. 2019 Jan 28;59(1):421-440. doi: 10.1021/acs.jcim.8b00805. Epub 2019 Jan 8.
The end-point methods like MM/PBSA or MM/GBSA estimate the free energy of a biomolecule by combining its molecular mechanics energy with solvation free energy and entropy terms. On the one hand, their performance largely depends on the particular system of interest, and despite numerous attempts to improve their reliability that have resulted in many variants, there is still no clear alternative to improve their accuracy. On the other hand, the relatively small cyclodextrin host-guest complexes, for which high-quality binding calorimetric data are usually available, are becoming reference models for testing the accuracy of free energy methods. In this work, we further assess the performance of various MM/PBSA-like approaches as applied to cyclodextrin complexes. To this end, we select a set of complexes between β-cyclodextrin and 57 small organic molecules that has been previously studied with the binding energy distribution analysis method in combination with an implicit solvent model ( Wickstrom, L.; He, P.; Gallicchio, E.; Levy, R. M. J. Chem. Theory Comput. 2013 , 9 , 3136 - 3150 ). For each complex, a conventional 1.0 μs molecular dynamics simulation in explicit solvent is performed. Then we employ semiempirical quantum chemical calculations, several variants of the MM-PB(GB)SA methods, entropy estimations, etc., to assess the reliability of the end-point affinity calculations. The best end-point protocol in this study, which combines DFTB3 energies with entropy corrections, yields estimations of the binding free energies that still have substantial errors (RMSE = 2.2 kcal/mol), but it exhibits a good prediction capacity in terms of ligand ranking ( R = 0.66) that is close to or even better than that of rigorous free energy methodologies. Our results can be helpful to discriminate between the intrinsic limitations of the end-point methods and other sources of error, such as the underlying energy and continuum solvation methods.
终点方法（如 MM/PBSA 或 MM/GBSA）通过将分子力学能量与溶剂化自由能和熵项相结合，来估算生物分子的自由能。一方面，它们的性能在很大程度上取决于特定的研究体系，尽管已经进行了许多改进其可靠性的尝试，并由此产生了许多变体，但仍然没有明确的替代方法可以提高其准确性。另一方面，相对较小的环糊精主客体配合物，通常具有高质量的结合量热数据，成为测试自由能方法准确性的参考模型。在这项工作中，我们进一步评估了各种类似 MM/PBSA 的方法在环糊精配合物中的应用性能。为此，我们选择了一组先前使用结合能分布分析方法与隐溶剂模型（Wickstrom，L.；He，P.；Gallicchio，E.；Levy，R. M. J. Chem. Theory Comput. 2013, 9, 3136-3150）结合研究过的β-环糊精与 57 种小分子有机分子的复合物。对于每个复合物，在显式溶剂中进行常规的 1.0 μs 分子动力学模拟。然后，我们采用半经验量子化学计算、几种 MM-PB(GB)SA 方法的变体、熵估计等方法，评估终点亲和力计算的可靠性。在这项研究中，最好的终点方案是将 DFTB3 能量与熵校正相结合，得到的结合自由能估计仍然存在较大误差（RMSE = 2.2 kcal/mol），但在配体排序方面具有良好的预测能力（R = 0.66），接近甚至优于严格的自由能方法。我们的研究结果有助于区分终点方法的内在局限性和其他误差源，例如基础能量和连续溶剂化方法。
