Calculating protein-ligand binding affinities with MMPBSA: Method and error analysis.
Calculating protein-ligand binding affinities with MMPBSA: Method and error analysis.
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DOI：
10.1002/jcc.24467
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发表时间：
2016-10-15
影响因子：
3
通讯作者：
Luo, Ray
中科院分区：
文献类型：
--
作者：
Wang, Changhao;Nguyen, Peter H.;Pham, Kevin;Huynh, Danielle;Le, Thanh-Binh Nancy;Wang, Hongli;Ren, Pengyu;Luo, Ray
MMPBSA方法由于其效率和与实验的高度相关性而被广泛用于估计蛋白质-配体结合亲和力。在这里，我们研究了不同的计算替代方案对MMPBSA计算与实验一致性的影响。选择了具有高质量晶体结构和结合亲和力的七个受体家族。我们首先研究了非极性溶剂化模型的性能，发现现代的方法，分别模拟疏水和分散相互作用显着降低RMSD的计算相对结合亲和力。接下来分析Poisson-Boltzmann方法的数值设置。我们的数据表明，网格间距对MMPBSA计算质量的影响很小：网格间距为0.5埃时的数值误差已经小到可以忽略不计。我们进一步分析了不同的原子半径集和不同的分子表面定义的影响，发现与实验的一致性的微弱影响。溶质介电常数的影响也进行了分析：较高的介电常数一般提高与实验的整体协议，特别是高电荷的结合口袋。我们的数据还表明，收敛的模拟导致与实验的一致性略有下降。最后简要探讨了绝对结合自由能的估算方向。修正后的结合诱导重排自由能和结合熵损失，绝对结合亲和力的误差也显着减少时，现代非极性溶剂模型使用，虽然进一步的发展显然是必要的，以进一步改善MMPBSA方法。现代非极性溶剂模型，分别模拟溶剂化，疏水和分散相互作用显着降低均方根计算相对结合亲和力的分子力学泊松-玻尔兹曼表面积（MMPBSA）方法。
MMPBSA methods have become widely adopted in estimating protein-ligand binding affinities due to their efficiency and high correlation with experiment. Here we investigated different computational alternatives on their impact to the agreement of MMPBSA calculations with experiment. Seven receptor families with both high-quality crystal structures and binding affinities were selected. We first studied the performance of nonpolar solvation models and found that the modern approach that separately models hydrophobic and dispersion interactions dramatically reduces RMSD’s of computed relative binding affinities. The numerical setup of the Poisson-Boltzmann methods was analyzed next. Our data shows that the impact of grid spacing to the quality of MMPBSA calculations is small: the numerical error at the grid spacing of 0.5 Angstrom is already small enough to be negligible. We further analyzed the impact of different atomic radius sets and different molecular surface definitions and found weak influences on the agreement with experiment. The influence of solute dielectric constant was also analyzed: a higher dielectric constant generally improves the overall agreement with experiment, especially for highly charged binding pockets. Our data also show that the converged simulations cause slight reduction in the agreement with experiment. Finally we briefly explored the direction of estimating absolute binding free energies. Upon correction of the binding-induced rearrangement free energy and the binding entropy lost, the errors in absolute binding affinities are also reduced dramatically when the modern nonpolar solvent model was used, though further developments are apparently necessary to further improve the MMPBSA methods. The modern nonpolar solvent model that separately models solvation hydrophobic and dispersion interactions dramatically reduces RMSDs of computed relative binding affinities in Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) methods.
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影响因子：
3
作者：
DAVIS, ME;MCCAMMON, JA
通讯作者：
MCCAMMON, JA
影响因子：
2.9
作者：
BASHFORD, D;KARPLUS, M
通讯作者：
KARPLUS, M
影响因子：
3.3
作者：
Edinger, SR;Cortis, C;Friesner, RA
通讯作者：
Friesner, RA
影响因子：
5.5
作者：
Cai, Qin;Hsieh, Meng-Juei;Wang, Jun;Luo, Ray
通讯作者：
Luo, Ray
影响因子：
4.4
作者：
Dzubiella, J;Swanson, JMJ;McCammon, JA
通讯作者：
McCammon, JA