Accurate Predictions of Nonpolar Solvation Free Energies Require Explicit Consideration of Binding-Site Hydration
Accurate Predictions of Nonpolar Solvation Free Energies Require Explicit Consideration of Binding-Site Hydration
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DOI：
10.1021/ja202972m
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发表时间：
2011-08-24
影响因子：
15
通讯作者：
Ryde, Ulf
中科院分区：
文献类型：
--
作者：
Genheden, Samuel;Mikulskis, Paulius;Ryde, Ulf
连续溶剂化法经常被用来提高计算方法的效率来估计自由能。在本文中，我们评估了这些方法在配体与蛋白质结合时估计非极性溶剂化自由能变化的效果。考虑了三种不同近似水平的连续介质方法，即极化连续介质模型（PCM）、基于空腔和色散项（CD）的方法和基于溶剂可及表面积线性关系的方法（SASA）。在连续体方法中，采用严格的双解耦热力学积分作为基准。我们研究了四种具有不同溶剂暴露结合位点的蛋白质配体复合物，即苯酚与铁蛋白的结合，生物素类似物亲和素，2-氨基苯并咪唑与胰蛋白酶的结合，以及取代的半乳糖苷与半乳糖凝集素-3的结合。对于结合位点相对隐蔽的铁蛋白和亲和蛋白，尽管模拟和实验表明配体在结合时取代了几个水分子，但如果结合位点在非结合状态下禁止连续水填充，则连续体方法可以获得相当精确的非极性溶剂化自由能。对于更多溶剂暴露的胰蛋白酶和半乳糖凝集素-3结合位点，即使允许或禁止用连续水填充结合位点，也无法获得准确的连续估计。这表明连续统方法不能在广泛的不同溶剂暴露的系统上给出准确的自由能，因为它们缺乏结合位点水合作用的微观图像以及配体结合之前在结合位点的水分子熵的信息。因此，基于连续溶剂化方法的结合亲和估计将给出绝对结合能，根据所使用的方法，绝对结合能可能相差高达200 kJ/mol。此外，即使具有相同支架的配体之间的相对能量也可能相差高达75 kJ/mol。我们试图通过增加结合位点的溶剂暴露或结合位点的水化信息来改进连续溶剂化方法，结果至少对这一小组配合物是有希望的。
Continuum solvation methods are frequently used to increase the efficiency of computational methods to estimate free energies. In this paper, we have evaluated how well such methods estimate the nonpolar solvation free-energy change when a ligand binds to a protein. Three different continuum methods at various levels of approximation were considered, viz., the polarized continuum model (PCM), a method based on cavity and dispersion terms (CD), and a method based on a linear relation to the solvent-accessible surface area (SASA). Formally rigorous double-decoupling thermodynamic integration was used as a benchmark for the continuum methods. We have studied four protein-ligand complexes with binding sites of varying solvent exposure, namely the binding of phenol to ferritin, a biotin analogue to avidin, 2-aminobenzimidazole to trypsin, and a substituted galactoside to galectin-3. For ferritin and avidin, which have relatively hidden binding sites, rather accurate nonpolar solvation free energies could be obtained with the continuum methods if the binding site is prohibited to be filled by continuum water in the unbound state, even though the simulations and experiments show that the ligand replaces several water molecules upon binding. For the more solvent exposed binding sites of trypsin and galectin-3, no accurate continuum estimates could be obtained, even if the binding site was allowed or prohibited to be filled by continuum water. This shows that continuum methods fail to give accurate free energies on a wide range of systems with varying solvent exposure because they lack a microscopic picture of binding-site hydration as well as information about the entropy of water molecules that are in the binding site before the ligand binds. Consequently, binding affinity estimates based upon continuum solvation methods will give absolute binding energies that may differ by up to 200 kJ/mol depending on the method used. Moreover, even relative energies between ligands with the same scaffold may differ by up to 75 kJ/mol. We have tried to improve the continuum solvation methods by adding information about the solvent exposure of the binding site or the hydration of the binding site, and the results are promising at least for this small set of complexes.