Centre of New Technologies, University of Warsaw , Banacha 2c, 02-097 Warsaw, Poland.
J Chem Theory Comput. 2017 Jun 13;13(6):2762-2776. doi: 10.1021/acs.jctc.7b00247. Epub 2017 May 24.
Explicit and implicit solvent models have a proven record of delivering hydration free energies of small, druglike solutes in reasonable agreement with experiment. Hydration of macromolecules, such as proteins, is to a large extent uncharted territory, with few results shedding light on quantitative consistency between different solvent models, let alone their ability to reproduce real water. In this work, based on extensive explicit solvent simulations employing TIP3P and SPC/E water models we analyze hydration free energy changes between fixed conformations of 5 diverse proteins, including large multidomain structures. For the two solvent models we find better agreement in electrostatic rather than nonpolar contributions (RMSE of 2.3 and 2.7 kcal/mol, respectively), even though absolute values of the latter are typically an order of magnitude smaller. We also highlight the importance of finite size corrections to relative protein hydration free energies, which turn out to be rather large, on the order of several kcal/mol, and are necessary for proper interpretation of results obtained under periodic boundary conditions. We further compare gathered data with predictions of the implicit solvent approach based on the Poisson equation and the surface or volume based nonpolar term. We find definitely lesser consistency than between the two explicit models (RMSE between implicit and TIP3 results of 11.3 and 8.4 kcal/mol for electrostatic and nonpolar contributions, respectively). In the process we determine the value of the protein dielectric constant and the geometric model for the dielectric boundary that provide for the best agreement. Finally, we evaluate the usefulness of surface and volume based models of nonpolar contributions to hydration free energy of large biomolecules.
显式溶剂模型和隐式溶剂模型在将小分子药物类溶质的水合自由能合理地与实验结果吻合方面有着良好的记录。然而，对于像蛋白质这样的生物大分子的水合作用，在很大程度上仍然是未知的领域，几乎没有结果可以说明不同溶剂模型之间的定量一致性，更不用说它们复制真实水的能力了。在这项工作中，我们基于广泛的显式溶剂模拟，使用 TIP3P 和 SPC/E 水模型，分析了 5 种不同蛋白质（包括大型多结构域结构）固定构象之间的水合自由能变化。对于这两种溶剂模型，我们发现静电贡献的一致性要好于非极性贡献（分别为 2.3 和 2.7 kcal/mol 的 RMSE），尽管后者的绝对值通常小一个数量级。我们还强调了对相对蛋白质水合自由能进行有限尺寸修正的重要性，这些修正相当大，约为几个 kcal/mol，对于正确解释在周期性边界条件下获得的结果是必要的。我们还将收集到的数据与基于泊松方程和基于表面或体积的非极性项的隐式溶剂方法的预测进行了比较。我们发现，与两种显式模型之间的一致性相比，肯定要差一些（对于静电和非极性贡献，隐式和 TIP3 结果之间的 RMSE 分别为 11.3 和 8.4 kcal/mol）。在这个过程中，我们确定了蛋白质介电常数的值和介电边界的几何模型，以提供最佳的一致性。最后，我们评估了基于表面和体积的非极性贡献模型对大型生物分子水合自由能的有用性。
