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 \({\text{kcal}}/{\text{mol}}\) 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 \(2.65\) and \(1.72 {\text{kcal}}/{\text{mol}}\), 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，我们报告了作为 SAMPL8 盲挑战的一部分，各种滥用药物对葫芦-[8]-uril 的结合自由能计算。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。副本交换伞采样 (REUS) 方法与圆柱形约束一起使用，以增强主客体绑定的采样。结合自由能是通过从对称和圆柱形主体的一侧拉动客体分子，然后进入并穿过主体，再从另一侧（双向）拉出来计算的，与仅拉动到圆柱形主体内部的结合姿势（单向）相比）。具有力匹配 MP2 参数集的初始结果导致 RMSE 为 4.68 \({\text{kcal}}/{\text{mol}}\)从实验值。然而，CHARMM 广义力场参数和力匹配 PM6-D3H4 参数的后续研究从\(2.65\)和\(1.72 {\text{kcal}}/{\text{mol} }\)分别展示了 REUS 在精确计算结合自由能方面的潜力，给出了更合适的能量学描述。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，双向方法中的一个问题是主机两侧的轮廓不对称。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 显示出结合自由能计算的巨大前景。