Use of MM-PBSA in reproducing the binding free energies to HIV-1 RT of TIBO derivatives and predicting the binding mode to HIV-1 RT of efavirenz by docking and MM-PBSA.
Use of MM-PBSA in reproducing the binding free energies to HIV-1 RT of TIBO derivatives and predicting the binding mode to HIV-1 RT of efavirenz by docking and MM-PBSA.
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DOI：
10.1021/ja003834q
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发表时间：
2001-05
影响因子：
15
通讯作者：
Junmei Wang;Paul Morin;Wei Wang;P. Kollman
中科院分区：
文献类型：
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作者：
Junmei Wang;Paul Morin;Wei Wang;P. Kollman
在这项工作中，提出了一种新的 ansatz，它将分子动力学模拟与 MM-PBSA（分子力学泊松-玻尔兹曼/表面积）相结合，对 12 种 TIBO 样 HIV-1 RT 抑制剂的结合亲和力进行排序。不仅在相对结合自由能方面取得了令人鼓舞的结果，而且在绝对结合自由能方面也取得了令人鼓舞的结果，其均方根偏差为 1.0 kcal/mol（最大误差为 1.89 kcal/mol）。由于均方根误差相当小，因此该方法可以可靠地应用于对数据库中这一重要靶标的配体进行排序。受到这些结果的鼓舞，我们决定应用 MM-PBSA 结合分子对接来确定依非韦伦 SUSTIVA(TM) 的结合模式，另一种有前途的 HIV-1 RT 抑制剂，在这项工作时尚未发表其配体-蛋白质晶体结构。首先，我们定义以下 ansatz：首先对 DOCK 4.0 建议的五种结合模式进行 500 皮秒分子动力学模拟，然后对收集的快照进行 MM-PBSA。 MM-PBSA 成功识别出正确的结合模式，其结合自由能比第二最佳模式高约 7 kcal/mol。此外，计算的结合自由能（-13.2 kcal/mol）与实验（-11.6 kcal/mol）相当一致。此外，该程序在对复合物进行建模方面也非常成功，并且最后快照的结构与测量的2,3 A分辨率晶体的结构非常接近（结构结合位点和抑制剂周围的54 C（α）的均方根偏差为1.1 A）。我们想指出的是，这一结果是在事先不了解依非韦伦/RT 复合物结构的情况下获得的。因此，分子对接与 MD 模拟相结合，然后进行 MM-PBSA 分析是先验模拟蛋白质复合物的一种有吸引力的方法。
In this work, a new ansatz is presented that combines molecular dynamics simulations with MM-PBSA (Molecular Mechanics Poisson-Boltzmann/surface area) to rank the binding affinities of 12 TIBO-like HIV-1 RT inhibitors. Encouraging results have been obtained not only for the relative binding free energies, but also for the absolute ones, which have a root-mean-square deviation of 1.0 kcal/mol (the maximum error is 1.89 kcal/mol). Since the root-mean-square error is rather small, this approach can be reliably applied in ranking the ligands from the databases for this important target. Encouraged by the results, we decided to apply MM-PBSA combined with molecular docking to determine the binding mode of efavirenz SUSTIVA(TM) another promising HIV-1 RT inhibitor for which no ligand-protein crystal structure had been published at the time of this work. To proceed, we define the following ansatz: Five hundred picosecond molecular dynamics simulations were first performed for the five binding modes suggested by DOCK 4.0, and then MM-PBSA was carried out for the collected snapshots. MM-PBSA successfully identified the correct binding mode, which has a binding free energy about 7 kcal/mol more favorable than the second best mode. Moreover, the calculated binding free energy (-13.2 kcal/mol) is in reasonable agreement with experiment (-11.6 kcal/mol). In addition, this procedure was also quite successful in modeling the complex and the structure of the last snapshot was quite close to that of the measured 2,3 A resolution crystal (structure the root-mean-square deviation of the 54 C(alpha) around the binding site and the inhibitor is 1.1 A). We want to point out that this result was achieved without prior knowledge of the structure of the efavirenz/RT complex. Therefore, molecular docking combined with MD simulations followed by MM-PBSA analysis is an attractive approach for modeling protein complexes a priori.