Protein-Ligand Electrostatic Binding Free Energies from Explicit and Implicit Solvation
Protein-Ligand Electrostatic Binding Free Energies from Explicit and Implicit Solvation
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DOI：
10.1021/acs.jctc.5b00483
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发表时间：
2015-09-01
影响因子：
5.5
通讯作者：
Onufriev, Alexey V.
中科院分区：
文献类型：
--
作者：
Izadi, Saeed;Aguilar, Boris;Onufriev, Alexey V.
准确而高效的溶剂环境计算模型是大多数依赖于原子模型的计算的核心，例如蛋白质配体结合亲和力的预测。在这项研究中，我们评估了最近发展的广义Born隐式溶剂模型GBNSR6 （Aguilar et al.）的准确性。j .化学。理论计算，2010,6,3613-3639)，在估计小蛋白质配体配合物的静电溶剂化自由能（δ G(pol)）和结合自由能（δ δ G(pol)）。我们还比较了基于三种不同的显式溶剂模型（TIP3P， TIP4PEw和OPC）的估计。两个主要发现如下。首先，GBNSR6结合亲和力与常用TIP3P参考值的偏差（RMSD = 7.04 kcal/mol）与显式模型之间的偏差相当，例如TIP4PEw与TIP3P （RMSD = 5.30 kcal/mol）。通过单一比例因子对原子半径进行简单的均匀调整，可以将GBNSR6与TIP3P的EMS偏差降低到上述“误差范围”内-不同常见显式溶剂模型估计的Delta Delta G（pol）之间的差异。简单的半径缩放几乎消除了GBNSR6与三个显式水模型中的两个模型之间的系统偏差（Delta Delta G(pol)），并显著降低了与第三个显式模型的偏差。其次，不同显式模型估算的静电结合能之间的差异大得令人不安；例如，TIP4PEw和TIP3P对δ δ G（pol）值的估计之间的偏差可能高达接近50%或接近9 kcal/mol，这明显大于接近1 kcal/mol的“化学准确度”目标。不同显式模型计算的绝对δ G（pol）相差可达数十千卡/摩尔。这些差异表明，结合亲和度估计对共同显式水模型的选择具有不可接受的高敏感性。在这些模型中缺乏明确的“金标准”，这加强了使用精确的隐式溶剂化模型来研究结合能的情况，这种模型可能要快几个数量级。
Accurate yet efficient computational models of solvent environment are central for most calculations that rely on atomistic modeling, such as prediction of protein-ligand binding affinities. In this study, we evaluate the accuracy of a recently developed generalized Born implicit solvent model, GBNSR6 (Aguilar et al. J. Chem. Theory Comput 2010, 6, 3613-3639), in estimating the electrostatic solvation free energies (Delta G(pol)) and binding free energies (Delta Delta G(pol)) for small protein-ligand complexes. We also compare estimates based on three different explicit solvent models (TIP3P, TIP4PEw, and OPC). The two main findings are as follows. First, the deviation (RMSD = 7.04 kcal/mol) of GBNSR6 binding affinities from commonly used TIP3P reference values is comparable to the deviations between explicit models themselves, e.g. TIP4PEw vs TIP3P (RMSD = 5.30 kcal/mol). A simple uniform adjustment of the atomic radii by a single scaling factor reduces the EMS deviation of GBNSR6 from TIP3P to within the above "error margin" - differences between Delta Delta G(pol) estimated by different common explicit solvent models. The simple radii scaling virtually eliminates the systematic deviation (Delta Delta G(pol)) between GBNSR6 and two out of the three explicit water models and significantly reduces the deviation from the third explicit model. Second, the differences between electrostatic binding energy estimates from different explicit models is disturbingly large; for example, the deviation between TIP4PEw and TIP3P estimates of Delta Delta G(pol) values can be up to similar to 50% or similar to 9 kcal/mol, which is significantly larger than the "chemical accuracy" goal of similar to 1 kcal/mol. The absolute Delta G(pol) calculated with different explicit models could differ by tens of kcal/mol. These discrepancies point to unacceptably high sensitivity of binding affinity estimates to the choice of common explicit water models. The absence of a clear "gold standard" among these models strengthens the case for the use of accurate implicit solvation models for binding energetics, which may be orders of magnitude faster.