Department of Theoretical Chemistry, Lund University, Chemical Centre, P.O. Box 124, SE-221 00 Lund, Sweden.
J Am Chem Soc. 2011 Aug 24;133(33):13081-92. doi: 10.1021/ja202972m. Epub 2011 Jul 29.
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.
连续溶剂化方法常用于提高计算方法估算自由能的效率。在本文中，我们评估了这些方法在配体与蛋白质结合时估算非极性溶剂化自由能变化的效果。考虑了三种不同的连续近似方法，即极化连续模型（PCM）、基于腔和色散项的方法（CD）以及基于与溶剂可及表面积线性关系的方法（SASA）。形式严格的双解耦热力学积分被用作连续方法的基准。我们研究了四个具有不同溶剂暴露程度的蛋白质-配体复合物，即苯酚与铁蛋白、生物素类似物与亲和素、2-氨基苯并咪唑与胰蛋白酶和取代半乳糖苷与半乳糖凝集素-3 的结合。对于铁蛋白和亲和素，其结合部位相对隐蔽，如果在非结合状态下禁止连续溶剂化水填充结合部位，则可以用连续溶剂化方法获得相当准确的非极性溶剂化自由能，尽管模拟和实验表明，配体结合后会取代几个水分子。对于胰蛋白酶和半乳糖凝集素-3 的更暴露溶剂化结合部位，即使允许或禁止结合部位被连续溶剂化水填充，也无法获得准确的连续溶剂化估算值。这表明，连续溶剂化方法无法在具有不同溶剂暴露程度的广泛系统中给出准确的自由能，因为它们缺乏对结合部位水合的微观描述，以及关于配体结合前位于结合部位的水分子的熵的信息。因此，基于连续溶剂化方法的结合亲和力估计将给出绝对结合能，这些结合能可能因方法而异，相差高达 200 kJ/mol。此外，即使是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。我们尝试通过添加关于结合部位溶剂暴露或结合部位水合的信息来改进连续溶剂化方法，至少对于这一小部分复合物，结果是有希望的。
