Expanded Ensemble Methods Can be Used to Accurately Predict Protein-Ligand Relative Binding Free Energies.
Expanded Ensemble Methods Can be Used to Accurately Predict Protein-Ligand Relative Binding Free Energies.
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DOI：
10.1021/acs.jctc.1c00513
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发表时间：
2021-10-12
影响因子：
5.5
通讯作者：
Voelz, Vincent A.
中科院分区：
文献类型：
--
作者：
Zhang, Si;Hahn, David F.;Shirts, Michael R.;Voelz, Vincent A.
炼金术的自由能方法已经成为不可或缺的计算药物的发现，他们的能力，计算高度准确的估计蛋白质配体的亲和力。扩展系综（EE）方法，它涉及单一的模拟访问所有的炼金术中间体，炼金术自由能计算有一些关键的优势。然而，在文献中发表的使用扩展系综模拟蛋白质-配体结合的自由能的例子相对较少。在本文中，作为扩展系综方法的测试，我们使用Open Force Field Initiative力场（代号“Parsley”）计算了源自16种化合物的同类系列的24对Tyk 2抑制剂的相对结合自由能。EE预测与实验值吻合良好（RMSE为0.94 ± 0.13 kcal mol−1，MUE为0.75 ± 0.12 kcal mol−1）。我们发现，虽然增加炼金中间体的数量可以改善相空间重叠，更快的收敛速度可以得到更少的中间体，只要接受率是足够的。我们还发现，收敛性可以提高使用更积极的更新的偏见，估计可以通过执行多个独立的EE计算。这项工作表明，EE是一个可行的选择炼金术自由能计算。我们讨论了这些发现对合理药物设计的影响，以及未来的改进方向。
Alchemical free energy methods have become indispensable in computational drug discovery for their ability to calculate highly accurate estimates of protein-ligand affinities. Expanded ensemble (EE) methods, which involve single simulations visiting all of the alchemical intermediates, have some key advantages for alchemical free energy calculation. However, there have been relatively few examples published in the literature of using expanded ensemble simulations for free energies of protein-ligand binding. In this paper, as a test of expanded ensemble methods, we compute relative binding free energies using the Open Force Field Initiative force field (codename “Parsley”) for twenty-four pairs of Tyk2 inhibitors derived from a congeneric series of 16 compounds. The EE predictions agree well with the experimental values (RMSE of 0.94 ± 0.13 kcal mol−1 and MUE of 0.75 ± 0.12 kcal mol−1). We find that while increasing the number of alchemical intermediates can improve the phase space overlap, faster convergence can be obtained with fewer intermediates, as long as the acceptance rates are sufficient. We also find that convergence can be improved using more aggressive updating of the biases, and that estimates can be improved by performing multiple independent EE calculations. This work demonstrates that EE is a viable option for alchemical free energy calculation. We discuss the implications of these findings for rational drug design, as well as future directions for improvement.
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