Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations.
Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations.
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评估 MM/PBSA 和 MM/GBSA 方法的性能。
DOI：
10.1021/ci100275a
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发表时间：
2011-01-24
影响因子：
5.6
通讯作者：
Wang, Wei
中科院分区：
文献类型：
--
作者：
Hou, Tingjun;Wang, Junmei;Li, Youyong;Wang, Wei
分子力学/泊松-玻尔兹曼表面积（MM/PBSA）和分子力学/广义玻尔兹曼表面积（MM/GBSA）方法通过结合分子力学计算和连续溶剂化模型来计算大分子的结合自由能。为了系统地评估这些方法的性能，我们在这里报告了59个配体与6种不同蛋白质相互作用的广泛研究。首先，我们探讨了长度的分子动力学（MD）模拟，范围从400到4800 ps，和溶质介电常数（1，2，或4）上的结合自由能预测MM/PBSA的影响。研究结果表明：（1）MD模拟长度对预测结果有明显的影响，并不一定需要更长的MD模拟时间才能获得更好的预测结果。(2)的预测是相当敏感的溶质介电常数，这个参数应仔细确定根据蛋白质/配体结合界面的特性。(3)构象熵通常在MD轨迹中显示出大的波动，并且需要大量的快照来实现稳定的预测。接下来，我们评估了由三种广义玻恩（GB）模型计算的结合自由能的准确性。我们发现，由Onufriev和Case开发的GB模型是对所研究的抑制剂的结合亲和力进行排名的最成功的模型。最后，我们评估了MM/GBSA和MM/PBSA在预测结合自由能方面的性能。我们的研究结果表明，MM/PBSA在计算绝对，但不一定是相对的，结合自由能比MM/GBSA更好。考虑到它的计算效率，MM/GBSA可以作为一个强大的工具，在药物设计中，抑制剂的正确排序往往是强调。
The Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) and the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) methods calculate binding free energies for macromolecules by combining molecular mechanics calculations and continuum solvation models. To systematically evaluate the performance of these methods, we report here an extensive study of 59 ligands interacting with six different proteins. First, we explored the effects of the length of the molecular dynamics (MD) simulation, ranging from 400 to 4800 ps, and the solute dielectric constant (1, 2, or 4) on the binding free energies predicted by MM/PBSA. The following three important conclusions could be observed: (1) MD simulation length has an obvious impact on the predictions, and longer MD simulation is not always necessary to achieve better predictions. (2) The predictions are quite sensitive to the solute dielectric constant, and this parameter should be carefully determined according to the characteristics of the protein/ligand binding interface. (3) Conformational entropy often show large fluctuations in MD trajectories, and a large number of snapshots are necessary to achieve stable predictions. Next, we evaluated the accuracy of the binding free energies calculated by three Generalized Born (GB) models. We found that the GB model developed by Onufriev and Case was the most successful model in ranking the binding affinities of the studied inhibitors. Finally, we evaluated the performance of MM/GBSA and MM/PBSA in predicting binding free energies. Our results showed that MM/PBSA performed better in calculating absolute, but not necessarily relative, binding free energies than MM/GBSA. Considering its computational efficiency, MM/GBSA can serve as a powerful tool in drug design, where correct ranking of inhibitors is often emphasized.
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影响因子：
4.1
作者：
GREEN, NM
通讯作者：
GREEN, NM
影响因子：
3
作者：
Feig, M;Onufriev, A;Brooks, CL
通讯作者：
Brooks, CL
影响因子：
3
作者：
Gohlke, H;Case, DA
通讯作者：
Case, DA
影响因子：
0.8
作者：
Batsanov, SS
通讯作者：
Batsanov, SS
影响因子：
3
作者：
Duan, Y;Wu, C;Kollman, P
通讯作者：
Kollman, P