We selected 145 reference organic molecules that include model fragments used in computer-aided drug design. We calculated 158 conformational energies and barriers using force fields, with wide applicability in commercial and free softwares and extensive application on the calculation of conformational energies of organic molecules, e.g. the UFF and DREIDING force fields, the Allinger’s force fields MM3-96, MM3-00, MM4-8, the MM2-91 clones MMX and MM+, the MMFF94 force field, MM4, ab initio Hartree–Fock (HF) theory with different basis sets, the standard density functional theory B3LYP, the second-order post-HF MP2 theory and the Domain-based Local Pair Natural Orbital Coupled Cluster DLPNO-CCSD(T) theory, with the latter used for accurate reference values. The data set of the organic molecules includes hydrocarbons, haloalkanes, conjugated compounds, and oxygen-, nitrogen-, phosphorus- and sulphur-containing compounds. We reviewed in detail the conformational aspects of these model organic molecules providing the current understanding of the steric and electronic factors that determine the stability of low energy conformers and the literature including previous experimental observations and calculated findings. While progress on the computer hardware allows the calculations of thousands of conformations for later use in drug design projects, this study is an update from previous classical studies that used, as reference values, experimental ones using a variety of methods and different environments. The lowest mean error against the DLPNO-CCSD(T) reference was calculated for MP2 (0.35 kcal mol⁻¹), followed by B3LYP (0.69 kcal mol⁻¹) and the HF theories (0.81–1.0 kcal mol⁻¹). As regards the force fields, the lowest errors were observed for the Allinger’s force fields MM3-00 (1.28 kcal mol⁻¹), ΜΜ3-96 (1.40 kcal mol⁻¹) and the Halgren’s MMFF94 force field (1.30 kcal mol⁻¹) and then for the MM2-91 clones MMX (1.77 kcal mol⁻¹) and MM+ (2.01 kcal mol⁻¹) and MM4 (2.05 kcal mol⁻¹). The DREIDING (3.63 kcal mol⁻¹) and UFF (3.77 kcal mol⁻¹) force fields have the lowest performance. These model organic molecules we used are often present as fragments in drug-like molecules. The values calculated using DLPNO-CCSD(T) make up a valuable data set for further comparisons and for improved force field parameterization.

Graphical abstract

中文翻译：

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参考有机分子的构象能：针对耦合簇理论的常见有效计算方法的基准测试

我们选择了 145 个参考有机分子，其中包括计算机辅助药物设计中使用的模型片段。我们利用力场计算了158种构象能和势垒，在商业和免费软件中具有广泛的适用性，并且广泛应用于有机分子构象能的计算，例如UFF和DREIDING力场、Allinger力场MM3-96、MM3- 00、MM4-8、MM2-91 克隆 MMX 和 MM+、MMFF94 力场、MM4、具有不同基组的从头算 Hartree–Fock (HF) 理论、标准密度泛函理论 B3LYP、二阶后 HF MP2理论和基于域的局域对自然轨道耦合簇DLPNO-CCSD(T)理论，后者用于精确参考值。有机分子的数据集包括碳氢化合物、卤代烷烃、共轭化合物以及含氧、氮、磷和硫的化合物。我们详细回顾了这些模型有机分子的构象方面，提供了对决定低能构象异构体稳定性的空间和电子因素的当前理解，以及包括以前的实验观察和计算结果在内的文献。虽然计算机硬件的进步允许计算数千种构象以供以后在药物设计项目中使用，但这项研究是对之前经典研究的更新，之前的经典研究使用各种方法和不同环境的实验结果作为参考值。相对于 DLPNO-CCSD(T) 参考的最低平均误差是针对 MP2 (0.35 kcal mol ⁻¹ ) 计算的，其次是 B3LYP (0.69 kcal mol ⁻¹ ) 和 HF 理论 (0.81–1.0 kcal mol ⁻¹ )。至于力场，观察到Allinger力场MM3-00（1.28 kcal mol ^-1）、μΜ3-96（1.40 kcal mol ^-1）和Halgren MMFF94力场（1.30 kcal mol ^-1）的误差最低。然后对于MM2-91克隆MMX (1.77 kcal mol ^-1 )和MM+ (2.01 kcal mol ^-1 )和MM4 (2.05 kcal mol ^-1 )。DREIDING (3.63 kcal mol ^-1 ) 和 UFF (3.77 kcal mol ^-1 ) 力场的性能最低。我们使用的这些模型有机分子通常以类药物分子的片段形式存在。使用 DLPNO-CCSD(T) 计算的值构成了一个有价值的数据集，可用于进一步比较和改进力场参数化。

图形概要