Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Department of Chemical and Biomolecular Engineering, University of Maryland, College Park, 20740, USA.
J Comput Aided Mol Des. 2021 May;35(5):667-677. doi: 10.1007/s10822-021-00385-7. Epub 2021 May 3.
In this study, we report binding free energy calculations of various drugs-of-abuse to Cucurbit-[8]-uril as part of the SAMPL8 blind challenge. Force-field parameters were obtained from force-matching with different quantum mechanical levels of theory. The Replica Exchange Umbrella Sampling (REUS) approach was used with a cylindrical restraint to enhance the sampling of host-guest binding. Binding free energy was calculated by pulling the guest molecule from one side of the symmetric and cylindrical host, then into and through the host, and out the other side (bidirectional) as compared to pulling only to the bound pose inside the cylindrical host (unidirectional). The initial results with force-matched MP2 parameter set led to RMSE of 4.68 [Formula: see text] from experimental values. However, the follow-up study with CHARMM generalized force field parameters and force-matched PM6-D3H4 parameters resulted in RMSEs from experiment of [Formula: see text] and [Formula: see text], respectively, which demonstrates the potential of REUS for accurate binding free energy calculation given a more suitable description of energetics. Moreover, we compared the free energies for the so called bidirectional and unidirectional free energy approach and found that the binding free energies were highly similar. However, one issue in the bidirectional approach is the asymmetry of profile on the two sides of the host. This is mainly due to the insufficient sampling for these larger systems and can be avoided by longer sampling simulations. Overall REUS shows great promise for binding free energy calculations.
在这项研究中，我们报告了各种滥用药物与葫芦[8]脲的结合自由能计算结果，这是 SAMPL8 盲测挑战的一部分。力场参数是通过与不同量子力学理论水平的力匹配获得的。复制交换伞状采样（REUS）方法与圆柱形约束一起使用，以增强主体 - 客体结合的采样。通过从对称和圆柱形主体的一侧将客体分子拉出，然后进入并穿过主体，然后从另一侧（双向）拉出，与仅将客体分子拉到圆柱形主体内的结合位置（单向）相比，计算结合自由能。使用力匹配的 MP2 参数集的初始结果导致 RMSE 为 4.68 [公式：见正文]，与实验值相比。然而，随后使用 CHARMM 广义力场参数和力匹配的 PM6-D3H4 参数进行的研究导致 RMSE 分别为实验值的 [公式：见正文]和 [公式：见正文]，这表明在更合适的能量描述下，REUS 具有准确计算结合自由能的潜力。此外，我们比较了所谓的双向和单向自由能方法的自由能，发现结合自由能非常相似。然而，双向方法的一个问题是主体两侧的轮廓不对称。这主要是由于这些较大系统的采样不足，可以通过更长的采样模拟来避免。总体而言，REUS 在结合自由能计算方面显示出巨大的潜力。
