State Key Laboratory of Precision Spectroscopy, School of Physics and Electronic Science, East China Normal University, Shanghai, 200062, China.
College of Engineering, Hebei Normal University, Shijiazhuang, 050024, China.
J Comput Aided Mol Des. 2021 Jan;35(1):117-129. doi: 10.1007/s10822-020-00351-9. Epub 2020 Oct 10.
The prediction of host-guest binding affinities with computational modelling is still a challenging task. In the 7th statistical assessment of the modeling of proteins and ligands (SAMPL) challenge, a new host named TrimerTrip was synthesized and the thermodynamic parameters of 16 structurally diverse guests binding to the host were characterized. In the TrimerTrip-guest challenge, only structures of the host and the guests are provided, which indicates that the predictions of both the binding poses and the binding affinities are under assessment. In this work, starting from the binding poses obtained from our previous enhanced sampling simulations in the configurational space, we perform extensive alchemical and end-point free energy calculations to calculate the host-guest binding affinities retrospectively. The alchemical predictions with two widely accepted charge schemes (i.e. AM1-BCC and RESP) are in good agreement with the experimental reference, while the end-point estimates perform poorly in reproducing the experimental binding affinities. Aside from the absolute value of the binding affinity, the rank of binding free energies is also crucial in drug design. Surprisingly, the end-point MM/PBSA method seems very powerful in reproducing the experimental rank of binding affinities. Although the length of our simulations is long and the intermediate spacing is dense, the convergence behavior is not very good, which may arise from the flexibility of the host molecule. Enhanced sampling techniques in the configurational space may be required to obtain fully converged sampling. Further, as the length of sampling in alchemical free energy calculations already achieves several hundred ns, performing direct simulations of the binding/unbinding event in the physical space could be more useful and insightful. More details about the binding pathway and mechanism could be obtained in this way. The nonequilibrium method could also be a nice choice if one insists to use the alchemical method, as the intermediate sampling is avoided to some extent.
用计算模型预测主体-客体结合亲和力仍然是一项具有挑战性的任务。在第 7 次蛋白质和配体建模的统计评估（SAMPL）挑战中，合成了一种名为 TrimerTrip 的新主体，并对 16 种结构不同的客体与主体结合的热力学参数进行了表征。在 TrimerTrip-客体挑战中，只提供了主体和客体的结构，这表明对结合构象和结合亲和力的预测都在评估之中。在这项工作中，我们从以前在构象空间中进行的增强采样模拟中得到的结合构象出发，进行了广泛的热力学计算，以回顾性地计算主体-客体结合亲和力。两种广泛接受的电荷方案（即 AM1-BCC 和 RESP）的热力学预测与实验参考值吻合良好，而终点估计在复制实验结合亲和力方面表现不佳。除了结合亲和力的绝对值外，结合自由能的秩在药物设计中也很关键。令人惊讶的是，终点 MM/PBSA 方法似乎在复制实验结合亲和力的秩方面非常有效。尽管我们的模拟长度很长，中间间隔很密，但收敛行为并不是很好，这可能是由于主体分子的灵活性所致。在构象空间中可能需要使用增强采样技术来获得完全收敛的采样。此外，由于在热力学自由能计算中的采样长度已经达到数百纳秒，因此在物理空间中直接模拟结合/解吸事件可能会更有用和有见地。通过这种方式，可以获得更多关于结合途径和机制的详细信息。如果坚持使用热力学方法，非平衡方法也可能是一个不错的选择，因为在一定程度上避免了中间采样。
