Calculations of Absolute Solvation Free Energies with TransformatoApplication to the FreeSolv Database Using the CGenFF Force Field

We recently introduced transformato, an open-source Python package for the automated setup of large-scale calculations of relative solvation and binding free energy differences. Here, we extend the capabilities of transformato to the calculation of absolute solvation free energy differences. After careful validation against the literature results and reference calculations with the PERT module of CHARMM, we used transformato to compute absolute solvation free energies for most molecules in the FreeSolv database (621 out of 642). The force field parameters were obtained with the program cgenff (v2.5.1), which derives missing parameters from the CHARMM general force field (CGenFF v4.6). A long-range correction for the Lennard-Jones interactions was added to all computed solvation free energies. The mean absolute error compared to the experimental data is 1.12 kcal/mol. Our results allow a detailed comparison between the AMBER and CHARMM general force fields and provide a more in-depth understanding of the capabilities and limitations of the CGenFF small molecule parameters.我们近期推出了transformato，一款用于自动化搭建相对溶剂化与结合自由能差大规模计算流程的开源Python软件包。本文中，我们将transformato的功能拓展至绝对溶剂化自由能差的计算范畴。在基于文献结果与使用CHARMM软件PERT模块（PERT module）开展的参考计算完成严谨验证后，我们使用transformato对FreeSolv数据库中642个分子中的621个的绝对溶剂化自由能进行了计算。力场参数通过cgenff程序（v2.5.1）获取，该程序可从CHARMM通用力场（CHARMM general force field，CGenFF v4.6）中推导缺失的参数。我们为所有计算得到的溶剂化自由能添加了伦纳德-琼斯（Lennard-Jones）相互作用的长程校正项。与实验数据相比，该结果的平均绝对误差为1.12 kcal/mol。本研究结果可实现AMBER与CHARMM通用力场间的细致对比，并能加深我们对CGenFF小分子参数的适用范围与局限性的理解。