Understanding Conformational Entropy in Small Molecules
Understanding Conformational Entropy in Small Molecules
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DOI：
10.1021/acs.jctc.0c01213
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发表时间：
2021-03-24
影响因子：
5.5
通讯作者：
Hutchison, Geoffrey R.
中科院分区：
文献类型：
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作者：
Chan, Lucian;Morris, Garrett M.;Hutchison, Geoffrey R.
柔性分子的熵的计算可能具有挑战性，因为可能的构象异构体的数量会随着分子大小呈指数增长，并且许多低能构象异构体可能是热可接近的。人们提出了不同的方法来近似构象熵对分子标准熵的贡献，包括用所有可能的稳定构象进行热化学计算以及根据实验数据进行经验校正。我们对超过 120,000 个小分子进行了构象异构体采样，生成了约 1200 万个构象异构体，以开发模型来预测各种分子的构象熵。通过深入了解构象紊乱的本质，我们经过交叉验证的物理驱动统计模型得出的平均绝对误差类似于 4.8 J/mol 中心点 K，或在 300 K 时低于 0.4 kcal/mol。除了预测分子熵和自由能之外，该模型还表明大多数分子中的扭转之间存在高度相关性，通常被认为是独立的。虽然单个二面体旋转可能具有低能量势垒，但大多数分子的形状和化学功能必然与其扭转自由度相关，因此极大地限制了低能量构象的数量。我们的简单模型捕捉了这些相关性并增进了我们对小分子构象熵的理解。
The calculation of the entropy of flexible molecules can be challenging, since the number of possible conformers can grow exponentially with molecule size and many low-energy conformers may be thermally accessible. Different methods have been proposed to approximate the contribution of conformational entropy to the molecular standard entropy, including performing thermochemistry calculations with all possible stable conformations and developing empirical corrections from experimental data. We have performed conformer sampling on over 120,000 small molecules generating some 12 million conformers, to develop models to predict conformational entropy across a wide range of molecules. Using insight into the nature of conformational disorder, our cross-validated physically motivated statistical model gives a mean absolute error of similar to 4.8 J/mol center dot K or under 0.4 kcal/mol at 300 K. Beyond predicting molecular entropies and free energies, the model implies a high degree of correlation between torsions in most molecules, often assumed to be independent. While individual dihedral rotations may have low energetic barriers, the shape and chemical functionality of most molecules necessarily correlate their torsional degrees of freedom and hence restrict the number of low-energy conformations immensely. Our simple models capture these correlations and advance our understanding of small molecule conformational entropy.